生理学笔记

Chapter 1 Introduction

1.1 The Scope of Human Physiology

Physiology is the study of how living organisms function.

1.2 Internal Environment and Homeostasis

1.2.1 Body Organization

1.2.1.1 Tissue

Muscle cells and tissue

• Skeletal, Cardiac, Smooth muscle cell

Neurons and Nervous tissue

• Neuron controls other cell through conducting electrical signals

Epithelial Cells and Epithelium

• Cuboidal, Columnar, Squamous, Ciliated cells
• Simple, stratified epithelium

Connective-Tissue Cells and Connective Tissue

• Bone, Cartilage, adipose tissue; loose, dense connective tissue;
• Blood

1.2.1.2 Organs and Organ Systems

• Organs are composed of two or more of the four kinds of tissues arranged in various proportions and patterns.
• Organ system is a collection of organs that together perform an overall function.

1.2.2 Body Fluid Compartments

Intracellular fluid 细胞内液

• the fluid contained within all the cells of the body (67%).

Extracellular fluid 细胞外液

• plasma (20-25%) 血浆
• interstitial fluid (75-80%) 组织液

1.2.3 Homeostasis

Homeostasis was defined as a state of reasonably stable balance between physiological variables such as those just described. 体内平衡被定义为刚才描述的生理变量之间合理稳定的平衡状态。

Homeostasis is a state of dynamic constancy.

1.3 Homeostatic Control Systems in the Body

Homeostatic control systems

• Feedback control systems: negative / positive feedback
• Adaptation and Acclimatization 适应和顺应: Resetting of set points
• Feedforward control systems

1.4 Forms of Functional Regulations in Human Body

Neural Regulation: Reflexes 神经调节：反射

• stimulus–response sequences

Humoral Regulation 体液调节

Autoregulation 自身调节

Chapter 2 Basic Function of Cell

2.1 Movement of Molecules Across the Cell Membranes

2.1.1 Functional Structure of the Cell Membranes

The plasma membrane forms the cell’s flexible outer surface, separating the cell’s internal environment from the external environment: selective barrier and communication 质膜形成细胞柔韧的外表面，将细胞内部环境与外部环境分隔开：选择性屏障和通讯

The cytoplasm consists of all the cellular contents between the plasma membrane and the nucleus: cytosol and organelles 细胞质由质膜和细胞核之间的所有细胞内容物组成：细胞溶胶和细胞器

The nucleus is a large organelle that houses most of a cell’s DNA; Chromosome, a single molecule of DNA associated with several proteins, contains genes. 细胞核是一个⼤型细胞器，容纳了细胞的⼤部分 DNA；染色体是与几种蛋⽩质相关的单个 DNA 分子，包含基因

Functions

• Regulate the passage of substances into and out of cells and between cell organelles and cytosol. 调节物质进出细胞
• Detect chemical messengers arriving at the cell surface. 检测到达细胞表面的化学信使
• Link adjacent cells together by membrane junctions. 通过膜连接将相邻的细胞连接在⼀起
• Anchor cells to the extracellular matrix. 将细胞锚定于细胞外基质

2.1.1.1 Membrane Lipids

2.1.1.1.1 Membrane Structure

• The plasma membrane, a flexible yet sturdy barrier that surrounds and contains the cytoplasm of a cell. 质膜是一种灵活而坚固的屏障，包围并包含细胞的细胞质
• Membranes are fluid structures because the lipids and many of the proteins are free to rotate and move sideways in their own half of the bilayer. 膜是流体结构，因为脂质和许多蛋⽩质可以在双层膜的各自一半中自由旋转和侧向移动。
• All membranes consist of a double layer of lipid molecules in which proteins are embedded. The major membrane lipids are phospholipids 所有膜均由双层脂质分子组成，蛋⽩质嵌⼊其中。主要的膜脂是磷脂。

2.1.1.1.2 Phospholipids 磷脂

• Phospholipids are amphipathic molecules 磷脂是两亲性分子
  • Polar head and non-polar tail
• Lipid bilayer has the characteristics of a fluid 具有流体的特性
  • Without chemical bonds, and fatty acids tail can bend ⽆化学键，脂肪酸尾部可弯曲
• Cholesterol is inserted into the lipid bilayer 胆固醇插⼊脂质双层
  • limit the ordered packing of fatty acids 限制脂肪酸的有序堆积

2.1.1.1.3 Membrane Proteins

• Integral proteins extend into or through the lipid bilayer and are firmly embedded in it. Most integral proteins are transmembrane proteins, which means that they span the entire lipid bilayer and protrude into both the cytosol and extracellular fluid. 整合蛋白延伸至脂质双层内或穿过脂质双层，并牢固地嵌入其中。大多数整合蛋白都是跨膜蛋白，这意味着它们跨越整个脂质双层，并突出到细胞溶胶和细胞外液中。
• Peripheral proteins are attached to the polar heads of membrane lipids or to integral proteins at the inner or outer surface of the membrane. 外周蛋白附着在膜脂的极性头部或膜内表面或外表面的整合蛋白上。

2.1.1.1.4 The Fluid-Mosaic Model 流体镶嵌模型

• certain membrane proteins are anchored to cytoplasmic proteins 某些膜蛋⽩锚定在细胞质蛋⽩上
• Proteins are covalently linked with membrane lipids to form structures called “lipid rafts” 蛋白质与膜脂质共价连接，形成称为“脂筏”的结构

2.1.1.1.5 Membrane junctions

• Extracellular matrix-membrane 细胞外基质膜
  • Integrins 整合素
• Desmosomes 桥粒
  • Dense plaque: Cadherins 致密斑块：钙粘蛋⽩
• Tight junction 紧密连接
  • Limited to a disk-shaped area of the membrane 仅限于膜的圆盘状区域
• Gap junction 间隙连接
  • protein channels linking the cytosols of adjacent cells 连接相邻细胞胞质的蛋⽩质通道

2.1.1.2 Cell Organelles

Nucleus

• Nuclear envelope, nuclear pore, chromatin, nucleolus 核膜、核孔、染色质、核仁

Ribosome: protein factory 核糖体：蛋⽩质工厂

Endoplasmic reticulum 内质⽹

• protein folding, lipid, Calcium

Golgi Apparatus 高尔基体

Secretory vesicles 分泌囊泡

Endosome

Mitochondria: bioenergetic hub 线粒体：⽣物能量中⼼

Peroxisome 过氧化物酶体

Membrane-less organelles

• nuclear stress bodies, processing bodies (P bodies) and stress granules

2.1.2 Transmembrane Transport of Molecules

Transport through the cell membrane, either directly through the lipid bilayer or through the proteins, occurs by one of two basic processes:

• Passive transport, is a movement of ions or other substances across cell membranes from a region of their higher concentration-in the direction down the concentration gradient.

  Simple diffusion; Facilitated diffusion; Osmosis 简单扩散；协助扩散；渗透

• Active transport is a movement of ions or other substances across the membrane against a concentration gradient.

  Primary active transport; Secondary active transport 初级主动运输；次级主动运输

2.1.2.1 Simple Diffusion

The movement of molecules from one location to another solely as a result of their random thermal motion is known as diffusion. (The energy is from heat. Random movement with no preferred direction of movement) 分子从一个位置移动到另一个位置，完全是由于其随机热运动而发⽣的，这种现象称为扩散。（能量来自热量。随机运动，没有首选运动⽅向）

The rate at which a substance is transported across a membrane refers to the number of molecules that cross the membrane in a unit of time, which is called the flux. 物质穿过膜的速率是指单位时间内穿过膜的分子数量，称为通量。

The magnitude of the net flux depends on several factors: the magnitude of the driving force, the membrane surface area, and the permeability of the membrane 净通量的⼤⼩取决于几个因素：驱动⼒的⼤⼩、膜表面积和膜的渗透性

concentration difference 浓度差: the greater the concentration difference, the greater the magnitude of the net flux; ↑

temperature 温度: the higher the temperature,the greater the speed of molecular movement and the greater the net flux; ↑

mass of the molecule 分子质量: large molecules (for example,proteins) have a greater mass and lower speed than smaller molecules (for example, glucose) and thus have a smaller net flux; ↓

surface area 表面积: the greater the surface area between two regions, the greater the space available for diffusion and thus the greater the net flux; ↑

the medium 分子运动的介质: through which the molecules are moving-most polar molecules diffuse very slowly or not at all,whereas nonpolar molecules diffuse much more rapidly.

2.1.2.2 Facilitated Diffusion

• Like simple diffusion, molecules move across a membrane from high concentration to low concentration, or “downhill” in facilitated diffusion.
• Neither simple diffusion nor facilitated diffusion is coupled to ATP derived from metabolism.

2.1.2.2.1 Diffusion Through Ion Channels

Ions such as $Na^+, K^+, Cl^-, Ca^{2+}$ diffuse across plasma membranes at rates that are much faster than would be predicted from their very low solubility in membrane lipids.

Different cells have quite different permeabilities to these ions, whereas nonpolar substances have similar permeabilities. 不同细胞对这些离子的通透性有相当⼤的差异，而⾮极性物质的通透性则相似。

Ion channels show a selectivity for the type of ion that can pass through them. This selectivity is based partially on the channel diameter and partially on the charged and polar surfaces of the protein subunits that form the channel walls and electrically attract or repel the ions. 离子通道对能通过的离子类型具有选择性。这种选择性部分取决于通道直径，部分取决于形成通道壁的蛋⽩质亚基的带电和极性表面，这些表面以电⽅式吸引或排斥离子。

Effect of electrical forces on ion movement:

• Positive and negative charges are distributed unequally between the inside and outside the cell. Separation of electrical charge exist across the membrane, known as membrane potential. 跨膜存在电荷分离，称为膜电位。Membrane potential function as electrical force to influence the movement of ions across the membrane. 膜电位作为电⼒发挥作用，影响离子跨膜的运动。

• Both the concentration difference and the electrical difference of ion determine the magnitude and direction of ion movement. 离子的浓度差和电性差共同决定离子运动的⼤⼩和⽅向。

• These two driving forces are collectively known as electrochemical gradient across the membrane. 这两种驱动⼒统称为跨膜的电化学梯度。

An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts:

• The chemical gradient, or difference in solute concentration across a membrane.
• The electrical gradient, or difference in charge across a membrane.

Regulation of diffusion through ion channels

Three factors can alter the channel protein conformations:

• the binding of specific molecules to channel proteins may directly or indirectly produce either an change in the shape of the channel protein;such channels are termed ligand-gated channels, and the ligands that influence them are often chemical messengers. 特定分子与通道蛋⽩的结合可能直接或间接地导致通道蛋⽩形状的改变；这种通道被称为配体门控通道，影响它们的配体通常是化学信使。
• Changes in the membrane potential can cause movement of the charged regions on a channel protein, altering its shape: voltage-gated channels. 膜电位的变化可能导致通道蛋⽩上带电区域的移动，从而改变其形状：电压⻔控通道。
• Stretching the membrane may affect the conformation of some channel proteins: mechanically gated channels. 拉伸膜可能会影响某些通道蛋⽩的构象：机械门控通道。

2.1.2.2.2 Facilitated Diffusion via Carrier

The movement of substances through a membrane by transporter (carrier) is called mediated transport.

• The solute must first binds to a specific site of transporter. 溶质必须首先与转运蛋⽩的特定位点结合
• The molecules can move in either direction.
• Transporter share similar characteristic with ion channel, but low efficiency. 转运体与离子通道具有相似的特性，但效率较低。
• Transporter can be saturated. (All binding site are occupied) 转运蛋⽩可能饱和。（所有结合位点均被占据）

Three factors determine the magnitude of solute flux through a mediated-transport system:

• The extent to which the transporter binding sites are saturated 转运蛋⽩结合位点的饱和程度
• the number of transporters in the membrane 膜中的转运蛋⽩数量
• the rate at which the conformational change in the transport protein occurs 运输蛋⽩发⽣构象变化的速率

2.1.2.3 Active transport

• Moves a substance “uphill” across a membrane (against substance’s concentration gradient).
• Consumes ATP
• Needs transporter, or usually called pump
  • the direct use of ATP in primary active transport
  • the use of an ion concentration difference across a membrane to drive the process in secondary active transport

Primary Active Transport

• The transporter is an enzyme (ATPase) that catalyzes the breakdown of ATP and,in the process, phosphorylates itself. 转运蛋⽩是一种酶（ATPase），可催化 ATP 的分解，并在此过程中对其进行自身磷酸化。
• Phosphorylation of the transporter protein (covalent modulation) changes its conformation and affinity binding with solutes. 转运蛋⽩的磷酸化（共价调节）改变其构象和与溶质的亲和⼒结合。
• For example, $Na^+/K^+ATPase,Ca^{2+}-ATPase, H^+-ATPase,H^+/K^+ATPase$

Secondary Active Transport

• Moves ion (normally but not always $Na^+$) across a membrane through established electrochemical gradient
• Need transporter
• Transport of another molecule is also coupled to ion movement (piggyback).
• Both molecules bind to transporter.
• The creation and maintenance of electrochemical gradient relies on the ATPase.

2.1.2.4 Osmosis

Water (polar) diffuses across the plasma membranes of most cells very rapidly mediated by proteins known as aquaporins. ⽔（极性）在⽔通道蛋⽩的介导下⾮常迅速地扩散到⼤多数细胞的质膜上。

The net diffusion of water across a membrane is called osmosis. ⽔穿过膜的净扩散称为渗透。

Water concentration depends on the number of solute particles,regardless of chemical composition. ⽔的浓度取决于溶质粒子的数量，与化学成分无关。

The total solute particle concentration of a solution is known as its osmolarity. 溶液的总溶质颗粒浓度称为其渗透压。

When a solution containing solutes is separated from pure water by a semipermeable membrane, the pressure that must be applied to the solution to prevent the net flow of water into it is known as the osmotic pressure of the solution.

Extracellular osmolarity and cell shape

• Unequal distribution of charged ion between inside and outside the cell contributes to the osmolarity of extracellular fluid.
• A solution of nonpenetrating solute with the same osmolarity as normal extracellular fluid (about 300 mOsm) is said to be isotonic.
• Isotonic solution would not cause the change in cell shape.
• Hypertonic solution causes cells to shrink is, whereas hypotonic solution causes cells to swell.
• Penetrating solutes do not contribute to the tonicity of a solution.

All hypoosmotic solutions are also hypotonic, whereas a hyperosmotic solution can be hypertonic, isotonic, or hypotonic. 所有低渗溶液也都是低张的，而高渗溶液可以是高张的、等张的或低张的。如果溶质分子不能透过细胞膜时，等渗即意味着等张。

2.1.2.5 Endocytosis and Exocytosis

When living cells are observed under a light microscope,regions of the plasma membrane can be seen to fold into the cell, forming small pockets that pinch off to produce intracellular, membrane-bound vesicles that enclose a small volume of extracellular fluid. This process is known as endocytosis. 在光学显微镜下观察活细胞时，可以看到质膜区域折叠进⼊细胞，形成⼩⼝袋，这些⼝袋会收缩形成细胞内膜结合囊泡，囊泡内会包裹少量细胞外液。这个过程称为内吞作用。

A similar process in the reverse direction,known as exocytosis,occurs when membrane-bound vesicles in the cytoplasm fuse with the plasma membrane and release their contents to the outside of the cell. 当细胞质中的膜结合囊泡与质膜融合并将其内容物释放到细胞外部时，就会发⽣一个相反⽅向的类似过程，称为胞吐作用。

2.1.2.5.1 Transport of Molecules into Cells by Endocytosis

In pinocytosis also known as fluid endocytosis an endocytotic vesicle encloses a small volume of extracellular fluid. (soluble molecules) 在胞饮作用（也称为液体内吞作用）中，内吞囊泡包裹少量细胞外液。（可溶性分子）

In phagocytosis cells engulf bacteria or large particles such as cell debris from damaged tissues.(pathogens or debris) In receptor-mediated endocytosis certain molecules in the extracellular fluid bind to specific proteins on the outer surface of the plasma membrane.(specific ligands) 在吞噬作用中，细胞吞噬细菌或⼤颗粒，如受损组织的细胞碎⽚。（病原体或碎⽚）在受体介导的内吞作用
中，细胞外液中的某些分子与质膜外表面的特定蛋⽩质结合。（特定配体）

2.1.2.5.2 Transport of Molecules Out of Cells by Exocytosis

Exocytosis is basically endocytosis in reverse: vesicle inside the cell fuses with the plasma membrane and releases its contents into the extracellular fluid.

Exocytosis has three functions:

• to add components to the plasma membrane 向质膜添加成分
• to recycle receptors removed from the plasma membrane by endocytosis 回收通过内吞作用从质膜上去除的受体
• to secrete specific substances out of the cell and into the extracellular fluid 将特定物质分泌出细胞并进⼊细胞外液

2.2 Transmembrane Signal Transductions

2.2.1 Overview

The process by which intercellular chemical signals communicate with cells and thereby elicit a physiological response is called signal transduction. 细胞间化学信号与细胞通讯并从而引起生理反应的过程称为信号转导。

Signal transduction enables coordination of cell function:

• Cell division (proliferation)
• Cell development (differentiation)
• Secretion
• Contraction / relaxation
• Firing of nerves

Cellular Signalling

• Aberrant cellular signalling underlies disease processes 异常细胞信号是疾病过程的基础
• Many medications target to cellular signalling processes 许多药物针对的是细胞信号传导过程
• Improved knowledge of cellular signalling processes continues to identify novel targets for drug design and improved therapy 对细胞信号传导过程的了解不断提高，为药物设计和改善治疗提供了新的靶点

Intercellular Signals

• neurotransmitters and hormones 神经递质和激素
• proteins, e.g. insulin 蛋⽩质，例如胰岛素
• small peptides, e.g. bradykinin ⼩肽，例如缓激肽
• amino acids, e.g. glutamate 氨基酸，例如⾕氨酸
• steroids, e.g. oestrogen, testosterone 类固醇，例如雌激素、睾酮
• vitamins
• fatty acid derivatives, e.g. prostaglandins, leukotrienes 脂肪酸衍⽣物，例如前列腺素、⽩三烯
• gas, e.g. nitric oxide (NO), H2S

2.2.2 Receptors

• typically integral membrane protein at the plasma membrane 通常是质膜上的整合膜蛋⽩
• recognise and bind to specific chemicals (ligands) 识别并结合特定化学物质（配体）
• receptor numbers can be increased (up-regulation) and decreased (down-regulation) 受体数量可以增加（上调）或减少（下调）

• Specificity: Receptors show specificity for the messenger; that is,they generally bind only one messenger or a class of messengers. 特异性：受体对信使表现出特异性；也就是说，它们通常只与一种信使或一类信使结合
• Affinity: The strength of the binding between a messenger and its receptor 亲和⼒：信使与其受体之间的结合强度
• Saturation 饱和
• Competition 竞争

Ligands 配体

Ligands are chemical messengers which bind to receptor proteins

Agonist – ligand with two important properties 激动剂

Antagonist – ligand which blocks the receptor has affinity but not efficacy 拮抗剂

Six steps of cellular signalling

2.2.3 Signal Transduction pathway

Signal transduction pathways: The “signal”is the receptor activation, and “transduction” denotes the process by which a stimulus is transformed into a response.

Signal transduction pathways differ at the very outset for lipid-soluble and lipid-insoluble messengers, the receptors for these two broad chemical classes of messenger are in different locations-the former inside the cell and the latter in the plasma membrane of the cell.

2.2.3.1 Pathways Initiated by Lipid-Soluble Messengers

(Mediated by Intracellular Receptors)

Most lipid-soluble messengers are hormones like steroid hormones, the thyroid hormones,and the steroid derivative, 1,25-dihydroxy vitamin D3. Structurally these hormones are all closely related, and their receptors constitute the steroid hormone receptor “superfamily”. ⼤多数脂溶性信使都是激素，如类固醇激素、甲状腺激素和类固醇衍⽣物 1,25‑二羟基维⽣素 D3。从结构上看，这些激素都密切相关，它们的受体构成类固醇激素受体“超家族”。

The receptors are intracellular and are inactive when no messenger is bound to them; the inactive receptors are mainly in the cell nucleus 受体位于细胞内，当没有信使与其结合时，受体处于⾮活性状态；⾮活性受体主要位于细胞核中

Step of signalling

1. A receptor is located in the nucleus, the hormone diffuses into the nucleus and binds to it, forming a hormone-receptor complex. 受体位于细胞核内，激素扩散到细胞核内并与之结合，形成激素‑受体复合物
2. Inside the nucleus,the hormone-receptor complex functions as a transcription factor by binding to a region of DNA called the hormone response element (HRE), which is located at the beginning of a specific gene. 在细胞核内，激素受体复合物通过与位于特定基因起始处的称为激素反应元件（HRE）的 DNA 区域结合发挥转录因子的作用
3. Binding of the complex to the HRE activates or deactivates the gene, which affects transcription of mRNA and ultimately increases or decreases synthesis of the protein coded by the gene. 复合物与 HRE 的结合会激活或抑制基因，从而影响 mRNA 的转录，最终增加或减少基因编码的蛋⽩质的合成
4. The mRNA moves into the cytosol. mRNA 进⼊细胞质
5. The mRNA is translated by ribosomes to yield proteins. mRNA 由核糖体翻译产⽣蛋⽩质

Mechanism of Action for Steroid Hormones

• The receptors for steroid hormones are known as nuclear receptors. For the steroid hormone-receptor complex to activate (or deactivate) a particular gene, two complexes must bind to the HRE in a process called dimerization. 类固醇激素受体被称为核受体。类固醇激素受体复合物要激活（或停用）特定基因，必须有两个复合物与 HRE 结合，这个过程称为二聚化

2.2.3.2 Pathways Initiated by Water-Soluble Messengers

(Mediated by Membrane-Bound Receptors)

• Signal transduction mediated by G-protein-linked receptor G蛋⽩连接受体介导的信号转导
• Signal transduction mediated by ionotropic receptor 离子型受体介导的信号转导
• Signal transduction mediated by enzyme-linked receptor 酶联受体介导的信号转导

2.2.3.2.1 Signal transduction mediated by G-protein-linked receptor

• The signal transduction mediated by G-protein-linked receptor is achieved by the cascade activities of the membranous receptors,G protein,G protein effector, second messenger and other molecules in cell membrane and cytoplasm. G蛋⽩连接受体介导的信号转导是通过细胞膜和细胞质中的膜性受体、G蛋⽩、G蛋⽩效应物、第二信使等分子的级联作用来实现的
• G-Protein-linked receptor: The structure consisted by a peptide chain that traverses the membrane seven times,belong to the same family: 7- transmembrane receptors G蛋⽩连接受体：由一条穿过膜七次的肽链组成的结构，属于同一家族：7‑跨膜受体
• The conformation of the receptor changes after the ligand binding to them, and then activate G protein. 配体与其结合后，受体构象发⽣改变，从而激活G蛋⽩

G protein

• Bound to the receptor is a protein located on the inner (cytosolic) surface of the plasma membrane and belonging to the family of proteins known as G proteins. 与受体结合的蛋⽩质位于质膜内表面（胞质），属于 G 蛋⽩家族
• The binding of a first messenger to the receptor changes the conformation of the receptor. This change causes one of the three subunits of the G protein to link up with still another plasma-membrane protein, either an ion channel or an enzyme. 第一信使与受体的结合改变了受体的构象。这种变化导致 G 蛋⽩的三个亚基之一与另一个质膜蛋⽩（离子通道或酶）连接起来。
• These ion channels and enzymes are termed plasma membrane effector proteins since they mediate the next steps in the sequences of events leading to the cell’s response. 这些离子通道和酶被称为质膜效应蛋⽩，因为它们介导导致细胞反应的一系列事件的下一步。

G protein effector G蛋⽩效应器

• Enzymes can catalyse the generation of second messengers,such as adenylyl cyclase phospholipase c, guanylyl cyclase….. 酶可以催化第二信使的产⽣，例如腺苷酸环化酶、磷脂酶c、⻦苷酸环化酶……
• Ion channels 离子通道
• They mediate the next steps in the sequence of events leading to the cell’s response.

Second messenger

• First messengers: the intercellular chemical messengers that reach the cell from the extracellular fluid and bind to their specific receptors. 第一信使：从细胞外液到达细胞并与特定受体结合的细胞间化学信使
• Second messengers: substances that enter or are generated in the cytoplasm as a result of receptor activation by the first messengers. 第二信使：由于第一信使的受体激活而进⼊细胞质或在细胞质中产⽣的物质
• Serve as chemical relays from the plasma membrane to the biochemical machinery inside the cell.
• CAMP, IP3, DG, cGMP, $Ca^{2+}$

2.2.3.2.2 Signal Transduction Mediated by Ionotropic Receptor

• Ionotropic Receptors are a type of ligand-gated ion channel in which the ligand is a messenger that binds to a receptor.
• The binding of a messenger to the receptor / ion channel causes the channel to open, increasing the membrane’s permeability for that specific ion. 信使与受体/离子通道的结合导致通道打开，从而增加膜对该特定离子的通透性
• Open ion channels allow a specific ion or class of ions to move across the plasma membrane down its electrochemical gradient. 开放的离子通道允许特定离子或一类离子沿着电化学梯度穿过质膜
• Ion movement into or out of the cell can have two different effects on the target cell: (1) Ions entering and leaving can change the electrical properties of the cell and (2) entering ions can interact with proteins inside the cell to induce a response such as muscle contraction, secretion, change in metabolism, or altered transport of a substance. ）离子的进⼊和离开可以改变细胞的电特性，进⼊的离子可以与细胞内的蛋⽩质相互作用，引起肌⾁收缩、分泌、代谢变化或物质运输改变等反应。

2.2.3.2.3 Signal Transduction Mediated by Enzyme-linked Receptor

• The receptor side faces the interstitial fluid and the enzyme side faces the cytosol 受体一侧朝向间质液，酶一侧朝向细胞溶胶
• A messenger binds to the receptor, changing its conformation.
• The conformation change activates the tyrosine kinase. 构象变化激活酪氨酸激酶
• The tyrosine kinase then catalyses phosphorylation of an intracellular protein. 酪氨酸激酶催化细胞内蛋⽩质的磷酸化
• Phosphorylation of the protein changes its activity by covalent regulation, bringing about a response in the target cell. 蛋⽩质的磷酸化通过共价调节改变其活性，从而引起靶细胞的反应

2.3 Electrical Activities of the Cell

2.3.1 Basic Physical Principles of Bioelectricity

• The predominant solutes in the extracellular fluid are sodium and chloride ions. The intracellular fluid contains high concentrations of potassium ions and ionized nonpenetrating molecules, particularly proteins, with negatively charged side chains and phosphate compounds. 细胞外液中的主要溶质是钠离子和氯离子。细胞内液含有高浓度的钾离子和离子化的⾮渗透性分子，特别是侧链带负电荷的蛋⽩质和磷酸盐化合物
• According to the physical principle, the oppositely charged molecules will move toward each other.
• Plasma membrane separate the electrical charges with opposite sign.

Bioelectricity

• Separated electric charges of opposite sign have the potential to come together, which is called an electric potential (V), or a potential difference because it is determined by the difference in the amount of charge between two points.
• The movement of electric charge is called a current (I). The hindrance to electrical charge movement is known as resistance (R).
• The lipid layers of the plasma membrane (insulator) sperate two aqueous compartments (conductor): the intracellular fluid and the extracellular fluid.

2.3.2 Resting Potential

• All living cells have a potential difference across their plasma membrane.
• When the cell is at rest this potential difference is called the resting membrane potential of the cell A tiny excess of negative ions inside the cell and an excess of positive ions outside. 当细胞处于静⽌状态时，这种电位差称为细胞的静息膜电位。细胞内部有少量负离子过量，而细胞外部有⼤量的正离子过量
• Extracellular fluid is designated as the voltage reference point,and the polarity of the membrane potential is stated in terms of the sign of the excess charge on the inside of the cell by comparison. 以细胞外液为电压参考点，通过⽐较，以细胞内部过量电荷的符号来表⽰膜电位的极性
• The ion concentration difference between inside and outside of a cell is established due to $Na^+$/$K^+$-ATPase activity.
• One certain ion moves across the membrane creates the potential difference.
• The differences in membrane permeabilities to different ion determines their movement.

outflux: The concentration gradient (the chemical gradient)

influx: The electrical gradient

The equilibrium potential for $K^+$ in cell

A simple cell has a concentration of 150 mM $K^+$ inside and 5 mM $K^+$ outside. At these concentrations, the equilibrium potential for $K^+$ can be calculated out as -90mV.

If only $Na^+$ channels are open in plasma membrane, $Na^+$ flux will move under its electrochemical gradient as similar as $K^+$ does, but at reverse direction.

According to the Nernst equation, the $Na^+$ flux through open channels will tend to bring the membrane potential toward +60 mV at its typical concentration.

The greater the membrane permeability to an ion species, the greater the contribution that ion species will make to the membrane potential. 膜对离子种类的通透性越⼤，该离子种类对膜电位的贡献越⼤

The neuron compensates for the movement of $Na^+$ and $K^+$

• the resting potential is generated across the plasma membrane largely because of the movement of $K^+$out of the cell down its concentration gradient through open $K^+$channels (called leak $K^+$ channels)

• a small number of open $Na^+$ channels does pull the membrane potential slightly toward the $Na^+$ equilibrium potential.

• The $Na^+$/$K^+$-ATPase pump maintains the resting membrane potential

• A membrane enzyme actively transports ions to compensate for $Na^+$ and $K^+$​ leaks.

  The pump uses the energy of ATP to move $Na^+$ and $K^+$ against their electrochemical gradients. Three Nat ions are pumped out of the neuron for every two $K^+$ions that are pumped in (electrogenic pump).

2.3.3 Graded Potentials and Action Potentials

Transient changes in the membrane potential from its resting level produce electric signals. These signals occur in two forms: graded potentials and action potentials.

The membrane is said to be depolarized when its potential is less negative (closer to zero) than the resting level. Overshoot refers to a reversal of the membrane potential polarity-that is, when the inside of a cell becomes positive relative to the outside. When a membrane potential that has been depolarized returns toward the resting value, it is said to be repolarized. The membrane is hyperpolarized when the potential is more negative than the resting level. 当膜电位⽐静息⽔平更低（更接近于零）时，膜被称为去极化。过冲是指膜电位极性的逆转，即当细胞内部相对于外部变为正值时。当去极化的膜电位恢复到静息值时，它被称为复极化。当电位⽐静息⽔平更负时，膜是超极化的。

2.3.3.1 Graded Potentials

Result from a net gain of $Na^+$​ ions

• Small and confined to a localised small region of membrane ⼩且局限于膜的局部⼩区域
• The potential dissipates (in other words the charge leaks away from the membrane) 电位消散（换句话说，电荷从膜中泄漏）
• Ions are diluted down by the bulk of the intracellular fluid and $K^+$ moves out to restore the resting membrane potential
• Its size is dependent upon the strength of the stimulus. 它的⼤⼩取决于刺激的强度
• Areas downstream of the initial depolarisation are affected by the movement of these ions (i.e. these areas become depolarized). 初始去极化下游的区域受到这些离子运动的影响（即这些区域变得去极化）
• The larger the potential the further it will tend to travel. 电位越⼤，它趋向于传播得越远
• Depending upon the initiating event, graded potentials can occur in either a depolarizing or hyperpolarizing direction and their magnitude is related to the magnitude of the initiating event. 根据起始事件，分级电位可以发⽣在去极化或超极化⽅向，并且其幅度与起始事件的幅度有关
• The magnitude of the current decreases with the distance from the initial site of the potential change. 电流的⼤⼩随着距电位变化的初始位置的距离而减⼩
• Local current is decremental; that is, its amplitude decreases with increasing distance from the site of origin of the potential. The resulting change in membrane potential from resting level therefore also decreases with the distance from the potential’s site of origin. 局部电流是递减的，也就是说，其幅度随着与电位起源点距离的增加而减⼩。因此，膜电位相对于静息⽔平的变化也随着与电位起源点距离的增加而减⼩

2.3.3.2 The Action Potential

2.3.3.2.1 Properties of Action Potentials

Nerve and muscle cells as well as some endocrine, immune, and reproductive cells have plasma membranes capable of producing action potentials. These membranes are called excitable membranes, and their ability to generate action potentials is known as excitability. Whereas all cells are capable of conducting graded potentials, only excitable membranes can conduct action potentials. The propagation of action potentials is the mechanism used by the nervous system to communicate over long distances. 神经细胞、肌⾁细胞以及一些内分泌细胞、免疫细胞和⽣殖细胞具有能够产⽣动作电位的质膜。这些膜称为可兴奋膜，其产⽣动作电位的能⼒称为兴奋性。虽然所有细胞都能够传导分级电位，但只有可兴奋膜才能传导动作电位。动作电位的传播是神经系统用于长距离通信的机制。

2.3.3.2.2 Voltage-Gated Ion Channels

$Na^+$and $K^+$channels (voltage-gated) are similar in having sequences of charged amino acid residues in their structure that make the channels reversibly change shape in response to changes in membrane potential. When the membrane is at a negative potential (for example, at the resting membrane potential), both types of channels tend to close, whereas membrane depolarization tends to open them. ，它们的结构中都有带电氨基酸残基序列，这使得通道能够响应膜电位的变化而可逆地改变形状。当膜处于负电位（例如，处于静息膜电位）时，这两种类型的通道都倾向于关闭，而膜去极化则倾向于打开它们。

2.3.3.2.3 Action Potential Mechanism

1. Steady resting membrane potential is near EK, PK > PNa, due to leak $K^+$ channels. 由于 $K^+$ 通道泄漏，稳定静息膜电位接近 EK、PK > PNa。
2. Local membrane is brought to threshold voltage by a depolarizing stimulus. 局部膜通过去极化刺激达到阈值电压。
3. Current through opening voltage-gated $Na^+$ channels rapidly depolarizes the membrane, causing more $Na^+$ channels to open. 通过打开电压门控 $Na^+$ 通道的电流使膜快速去极化，导致更多 $Na^+$ 通道打开。
4. Inactivation of $Na^+$ channels and delayed opening of voltage-gated $K^+$ channels halt membrane depolarization. $Na^+$ 通道失活和电压门控 $K^+$ 通道延迟打开会阻止膜去极化。
5. Outward current through open voltage-gated $K^+$ channels repolarizes the membrane back to a negative potential. 通过开放电压门控 $K^+$ 通道的外向电流使膜重新极化回负电位。
6. Persistent current through slowly closing voltage-gated $K^+$ channels hyperpolarizes membrane toward EK; $Na^+$ channels return from inactivated state to closed state (without opening). 通过缓慢关闭电压门控 $K^+$ 通道的持续电流使膜向 EK 超极化； $Na^+$通道从失活状态返回到关闭状态（不打开）。
7. Closure of voltage-gated $K^+$ channels returns the membrane potential to its resting value. 电压门控 $K^+$ 通道的关闭使膜电位恢复至其静息值。

The depolarizing phase of the action potential is due to the opening of voltage-gated sodium channels, which increases the membrane permeability to sodium ions several hundredfold. (1) the sodium channels that opened during the depolarization phase undergo inactivation near the peak of the action potential, which causes them to close; and (2) voltage-gated potassium channels, which open more slowly than sodium channels,open in response to the depolarization. 动作电位的去极化相是由于电压⻔控钠通道的开放，这使膜对钠离子的通透性增加了几百倍。（1）在去极化阶段打开的钠通道在动作电位峰值附近失活，导致其关闭；（2）电压⻔控钾通道⽐钠通道打开得慢，在去极化反应中打开。

Threshold and the All-or-None Response

• Action potentials occur only when the net movement of positive charge through ion channels is inward. The membrane potential at which this occurs is called the threshold potential, and stimuli that are just strong enough to depolarize the membrane to this level are threshold stimuli. 动作电位仅当正电荷通过离子通道的净运动向内时才会发⽣。发⽣这种情况的膜电位称为阈值电位，强度刚好足以使膜去极化到这个⽔平的刺激是阈值刺激。
• The threshold of most excitable membranes is about 15 mV less negative than the resting membrane potential. Thus, if the resting potential of a neuron is 70 mV, the threshold potential may be 55 mV. ⼤多数可兴奋膜的阈值⽐静息膜电位低约 15 mV。因此，如果神经元的静息电位为 70 mV，则阈值电位可能为 55 mV。
• At depolarizations less than threshold, outward potassium movement still exceeds sodium entry, and the positive-feedback cycle cannot get started despite the increase in sodium entry. In such cases, the membrane will return to its resting level as soon as the stimulus is removed, and no action potential is generated. These weak depolarizations are subthreshold potentials, and the stimuli that cause them are subthreshold stimuli. 当去极化低于阈值时，钾离子向外运动仍超过钠离子进⼊，尽管钠离子进⼊增加，正反馈循环仍无法启动。在这种情况下，一旦刺激消失，膜就会恢复到静息⽔平，不会产⽣动作电位。这些弱去极化是阈下电位，引起它们的刺激是阈下刺激。
• Changes in the membrane potential with increasing strength of depolarizing stimulus. When the membrane potential reaches threshold, action potentials are generated. Increasing the stimulus strength above threshold level does not cause larger action potentials. 将刺激强度增加到阈值以上不会引起更⼤的动作电位。
• Action potentials are all-or-none. The actual shape and amplitude of the action potential depends on the membrane conditions existing at a given time. 动作电位是全有或全无的。动作电位的实际形状和幅度取决于给定时间存在的膜条件。
• A single action potential cannot convey information about the magnitude of the stimulus that initiated it. 单个动作电位无法传达有关引发该动作电位的刺激幅度的信息。

2.3.3.2.4 Refractory Periods

• During the action potential, a second stimulus, no matter how strong, will not produce a second action potential, and the membrane is said to be in its absolute refractory period. (the voltage-gated $Na^+$ channels are inactivated) 在动作电位期间，第二个刺激无论多强都不会产⽣第二个动作电位，并且膜被称为处于绝对不应期（电压⻔控 Na+ 通道失活）
• Following the absolute refractory period, there is an interval during which a second action potential can be produced, but only if the stimulus strength is considerably greater than usual. This is the relative refractory period, which can last 10 to 15 ms or longer in neurons and coincides roughly with the period of afterhyperpolarization. (only partial $Na^+$ channels are recovered and $K^+$ permeability is still above resting period.) 绝对不应期之后，有一个间隔，在此期间可以产⽣第二个动作电位，但前提是刺激强度远高于平常。这是相对不应期，在神经元中可持续 10 到 15 毫秒或更长时间，⼤致与超极化后期相吻合（只有部分 Na+ 通道恢复，K+ 通透性仍高于静息期。）
• Supernormal period is most of after-depolarization potential when the threshold intensity is lower than normal value resulting from the membrane potential close to the threshold potential, and the action potential size is still less than the normal. 超正常期是指膜电位接近阈值电位时，其阈值强度低于正常值而引起的后去极化电位，而动作电位⼤⼩仍⼩于正常。
• Subnormal period is the last stage coincides roughly with the period of after-hyperpolarization. Large stimulus is needed to depolarize the membrane above the threshold potential due to the hyperpolarized membrane potential. 亚正常期是最后一个阶段，⼤致与超极化后期相吻合。由于膜电位超极化，需要很⼤的刺激才能使膜去极化到阈值电位以上。

2.3.3.2.5 Action Potential Propagation

How does the action potential move along the length of the axon? 动作电位如何沿着轴突的长度移动？

Propagation of Action Potentials in Unmyelinated Axons 无髓鞘轴突中动作电位的传播

• Action potential doesn’t move but “sets off” a new action potential in the region of the axon just ahead of it. 动作电位不会移动，但会在其前⽅的轴突区域“引发”新的动作电位。
• Excitable membranes are able to conduct action potentials in either direction, the direction of propagation being determined by the stimulus location. 可兴奋膜能够向任一⽅向传导动作电位，传播⽅向由刺激位置决定。
• The larger the fibre diameter, the faster the action potential propagates. 纤维直径越⼤，动作电位传播越快。

Why does myelination speed up conduction? (Saltatory Conduction) 为什么髓鞘形成会加速传导？（跳跃传导）

• In axons that are sheathed in myelin, action potentials are propagated by a specialized type of electrotonic conduction called saltatory conduction. 在被髓鞘包裹的轴突中，动作电位通过一种特殊类型的电紧张传导（称为跳跃传导）传播。
• The nodes of Ranvier are gaps in the myelin where the axon membrane lacks insulation, is exposed to the interstitial fluid, and has a high concentration of voltage gated sodium and potassium channels. 郎⻜⽒结是髓鞘中的空隙，其中轴突膜缺乏绝缘，暴露于间质液，并且具有高浓度的电压⻔控钠通道和钾通道。
• The separation of charge in the intracellular fluid causes current to flow from one node of Ranvier to the next. 细胞内液中电荷的分离导致电流从一个郎⻜⽒结流向另一个郎⻜⽒结。

2.3.4 Synapses

Transmitter 神经递质:

• diffusible molecule 扩散分子
• released from nerve terminal 从神经末梢释放
• triggers response in innervated cell 触发受支配细胞的反应

Recepter:

• chemical group on cell surface
• part of protein molecule
• binds transmitter
• mediates response

1. Calcium channels open when the axon terminal is depolarized. 当轴突末端去极化时，钙通道开放
2. More calcium ions flow into the axon terminal. 更多的钙离子流⼊轴突末端
3. Calcium causes synaptic vesicles to release the neurotransmitters into the synaptic cleft. 钙导致突触⼩泡释放神经递质进⼊突触间隙
4. Neurotransmitter molecules bind to receptors and 神经递质分子与受体结合
5. induce next response.
6. Some neurotransmitter molecules are degraded by enzymes. 一些神经递质分子被酶降解
7. Neurotransmitter molecules can be reuptaked into the presynaptic neuron 神经递质分子可以被重新吸收到突触前神经元中
8. others simply diffuse out of the cleft. 其余的则从裂缝中扩散出来

Signal Transduction Mechanisms at Chemical Synapses 化学突触的信号转导机制

• The binding of the neurotransmitter opens the ion channel and changes the electrical properties of the postsynaptic neuron. The typical response is a change in the membrane potential, called a postsynaptic potential (PSP). 神经递质的结合会打开离⼦通道并改变突触后神经元的电特性。典型的反应是膜电位的变化，称为突触后电位 (PSP)
• An excitatory synapse is one that brings the membrane potential of the postsynaptic neuron closer to the threshold for generating an action potential. This depolarization, which is called an excitatory postsynaptic potential (EPSP). 兴奋性突触使突触后神经元的膜电位更接近产生动作电位的阈值。这种去极化被称为兴奋性突触后电位 (EPSP)
• An inhibitory synapse is one that decreases the likelihood that an action potential will be generated in the postsynaptic neuron. When a neurotransmitter causes potassium channels to open,potassium will move out of the cell, hyperpolarizing it. This hyperpolarization is called an
  inhibitory postsynaptic potential (IPSP) . 抑制性突触会降低突触后神经元产生动作电位的可能性。当神经递质导致钾通道打开时，钾会移出细胞，使细胞超极化。这种超极化称为抑制性突触后电位 (IPSP)

2.4 Muscular Contraction

2.4.1 Skeletal Characteristics

The contractile cells of the body can be classified into three major groups based on their shape, number and position of nuclei, presence of striations and whether they are under voluntary or involuntary control. 根据收缩细胞的形状、细胞核的数量和位置、是否有条纹以及是否受自主或⾮自主控制，可将人体的收缩细胞分为三大类。

The term muscle refers to a number of muscle fibres bound together by connective tissue. Muscles are usually linked to bones by bundles of collagen fibres known as tendons, which are located at each end of the muscle. 肌⾁一词指的是通过结缔组织结合在一起的多条肌⾁纤维。肌⾁通常通过位于肌⾁两端的胶原纤维束（称为肌腱）与⻣骼连接。

2.4.1.1 Skeletal Muscle

• The most striking feature seen when observing skeletal-or cardiac-muscle fibres through a light microscope is a series of light and dark bands perpendicular to the long axis of the fibre. Because of this characteristic banding, both types are known as striated muscle. ⽤光学显微镜观察⻣骼肌或⼼肌纤维时，最显著的特征是一系列垂直于纤维长轴的明暗带。由于这种特征性带状结构，这两种类型的肌纤维都被称为横纹肌。
• The striated pattern in skeletal and cardiac fibres results from the arrangement of numerous thick and thin filaments in the cytoplasm into approximately cylindrical bundles (1 to 2 um in diameter) known as myofibrils. ⻣骼纤维和⼼脏纤维中的条纹图案是由细胞质中⽆数根粗细不同的细丝排列成近似圆柱形的束（直径 1 至 2 微米），称为肌原纤维。
• Most of the cytoplasm of a fibre is filled with myofibrils,each of which extends from one end of the fibre to the other and is linked to the tendons at the ends of the fibre. 纤维的细胞质中大部分充满着肌原纤维，每根肌原纤维从纤维的一端延伸到另一端，并与纤维末端的肌腱相连。

2.4.1.2 Muscle fibre (single muscle cell) 肌纤维（单个肌细胞）

The thick and thin filaments in each myofibril are arranged in a repeating pattern along the length of the myofibril. One unit of this repeating pattern is known as a sarcomere. 每根肌原纤维中的粗肌丝和细肌丝沿着肌原纤维的长度以重复的方式排列。这种重复模式的一个单位称为肌节。

Structure of Myofibril 肌原纤维的结构

• The thick filaments are composed almost entirely of the contractile protein myosin. 粗丝几乎完全由收缩蛋白肌球蛋白组成。
• The thin filaments (which are about half the diameter of the thick filaments) contain the contractile protein actin, as well as to two other proteins - troponin and tropomyosin - that play important roles in regulating contraction. 细丝（其直径约为粗丝的一半）含有收缩蛋白肌动蛋白，以及其他两种蛋白质肌钙蛋白和原肌球蛋白，它们在调节收缩中发挥重要作⽤。

Arrangements of Myofilaments 肌丝的排列

• The arrangement of thick and thin myofilaments forms the light and dark bands (striations) along the myofibril. 粗肌丝和细肌丝的排列沿着肌原纤维形成明带和暗带（条纹）。
• The thick filaments are located in the middle of each sarcomere, where their orderly parallel arrangement produces a wide, dark band known as the A band. 粗肌丝位于每个肌节的中间，它们有序的平行排列形成一条宽而暗的带，称为 A 带。
• Each sarcomere contains two sets of thin filaments, one at each end. One end of each thin filament is anchored to a network of interconnecting proteins known as the Z line, whereas the other end overlaps a portion of the thick filaments. 每个肌节包含两组细丝，每组位于两端。每组细丝的一端锚定在称为 Z 线的互连蛋白质⽹络上，而另一端与粗丝的一部分重叠。

Structure of Myofibril 肌原纤维的结构

• A light band, known as the I band, lies between the ends of the A bands of two adjacent sarcomeres and contains those portions of the thin filaments that do not overlap the thick filaments. 一条亮带（称为 I 带）位于两个相邻肌节的 A 带末端之间，包含不与粗肌丝重叠的细肌丝部分。
• The H zone is a narrow light band in the centre of the A band. It corresponds to the space between the opposing ends of the two sets of thin filaments in each sarcomere. H 区是 A 带中⼼的一条窄光带。它对应于每个肌节中两组细丝相对两端之间的空间。
• A narrow, dark band in the centre of the H zone is known as the M line and corresponds to proteins that link together the central region of the thick filaments. H 区中⼼的一条狭窄的暗带被称为 M 线，对应于连接粗丝中⼼区域的蛋白质。

2.4.2 Mechanism of striated muscle contraction

2.4.2.1 Neuromuscular Junction

The Sliding Filament Theory: The contraction of a muscle cell occurs as the thin filaments slide past the thick filaments.

1. Ach is synthesized in the cytosol of the axon terminals of neurons. Ach 在神经元轴突末端的胞质溶胶中合成。

   

2. Ach is transported into and stored in synaptic vesicles. Ach 被运输到突触小泡中并储存在其中。

3. An action potential triggers its release by exocytosis into synapse cleft. 动作电位触发其通过胞吐作⽤释放到突触间隙。

4. Ach can bind to receptors on the postsynaptic cell. Ach可以与突触后细胞上的受体结合。

5. Ach can be degraded into choline and acetate by an enzyme called acetylcholinesterase (AChE). 乙酰胆碱可以被一种叫做乙酰胆碱酯酶的酶降解为胆碱和醋酸盐。

6. Choline is taken back into the presynaptic cell and can be used to synthesize more acetylcholine. The acetate diffuses away from the synapse and enters the bloodstream. 胆碱被带回突触前细胞，可⽤于合成更多乙酰胆碱。醋酸盐从突触扩散并进⼊⾎液。

2.4.2.2 Excitation–Contraction Coupling 兴奋‑收缩耦合

At the end of sarcoplasmic reticulum there are two enlarged regions, known as lateral sacs that are connected to each other by a series of smaller tubular elements. The lateral sacs store the calcium that is released following membrane excitation. 肌浆⽹末端有两个扩大的区域，称为侧囊，它们通过一系列较小的管状元件相互连接。侧囊储存膜兴奋后释放的钙。

A separate tubular structure, the transverse tubule (T tubule), passing between adjacent lateral sacs and eventually joining the plasma membrane The lumen of the T tubule is continuous with the extracellular fluid surrounding the muscle fibre. The membrane of the T tubule is able to propagate action potentials. 横小管（T 小管）是一种独⽴的管状结构，它穿过相邻的侧囊，最终与质膜相连。T 小管的管腔与肌纤维周围的细胞外液相连。T 小管的膜能够传播动作电位。

1. Once initiated in the plasma membrane,an action potential is rapidly conducted over the surface of the fibre and into its interior by way of the T tubules. 一旦在质膜上启动，动作电位就会迅速传导通过 T 小管从纤维表面进⼊其内部。
2. The action potential in a T tubule adjacent to the lateral sacs activates voltage-gated proteins in the T-tubule membrane that are physically or chemically linked to calcium- release channels in the membrane of the lateral sacs. 毗邻侧囊的 T 小管中的动作电位激活 T 小管膜中的电压⻔控蛋白，这些蛋白在物理或化学上与侧囊膜中的钙释放通道相连。
3. Depolarization of the T tubule by an action potential thus leads to the opening of the calcium channels in the lateral sacs, allowing calcium to diffuse from the calcium-rich lumen of the lateral sacs into the cytosol. The rise in cytosolic calcium concentration is normally enough to turn on all the cross bridges in the fibre. 动作电位使 T 小管去极化，从而导致侧囊中的钙通道打开，使钙从侧囊富含钙的腔内扩散到细胞质中。细胞质钙浓度的升⾼通常足以打开纤维中的所有横桥。
4. A contraction continues until calcium is removed from troponin,and this is achieved by lowering the calcium concentration in the cytosol back to its pre-release level. 收缩持续直至钙从肌钙蛋白中去除，这是通过将细胞溶胶中的钙浓度降低回其释放前的水平来实现的。
5. The cytosolic calcium concentration remains elevated,and the contraction continues for some time after a single action potential. 细胞质钙浓度保持升⾼，并且单个动作电位后收缩会持续一段时间。

What cytoplasmic $Ca^{2+}$ did? 细胞质 Ca2+ 起了什么作⽤？

• An action potential brings about the release of $Ca^{2+}$ from the terminal cisternae of the sarcoplasmic reticulum. 动作电位导致 Ca2+ 从肌浆⽹末端池中释放。
• $Ca^{2+}$ flood into the cytosol and bind to the troponin, causing a change in the conformation of the troponin-tropomyosin complex. Ca2+涌⼊细胞质并与肌钙蛋白结合，导致肌钙蛋白‑原肌球蛋白复合物构象发生改变。
• This conformational change exposes the binding sites on actin. 这种构象变化暴露了肌动蛋白上的结合位点。

2.4.2.3 Molecular Mechanisms of Skeletal Muscle Contraction: Sliding-Filament Mechanism

In skeletal muscle myosin molecules are bundled together to form thick filaments. 在⻣骼肌中，肌球蛋白分⼦捆绑在一起形成粗丝。

Myosin 肌球蛋白

• The shape of an individual myosin molecule is similar to a golf club with two heads. 单个肌球蛋白分⼦的形状类似于具有两个头的⾼尔夫球杆。
• The heads (cross bridge) have the ability to move back and forth. 头部（横桥）具有前后移动的能⼒。
• The flexing movement of the head provides the ‘power for muscle contraction. 头部的屈曲运动为肌⾁收缩提供了动⼒。
• The hinge portion of the tail allows for movement so that the cross bridge can bind to actin (thin filament). 尾部的铰链部分允许运动，以便横桥可以与肌动蛋白（细丝）结合。

The cross bridge has two important binding sites 肌动蛋白结合位点 ATP结合位点. One site specifically binds ATP. Note the position of the cross bridge. This is called the low-energy conformation 低能构象. The binding of ATP transfers energy to the myosin cross bridge as ATP is hydrolysed into ADP and Pi. The binding site on the myosin cross bridge has a strong attraction for binding to actin.

Actin 肌动蛋白

• The thin filament consists of actin subunits arranged into a double helical chain. Each actin subunit has a specific binding site to which myosin cross bridges bind. 细丝由排列成双螺旋链的肌动蛋白亚基组成。每个肌动蛋白亚基都有⼀个特定的结合位点，肌球蛋白交叉桥可以与其结合。

Tropomyosin 原肌球蛋白

The regulatory protein tropomyosin is also part of the thin filament. Tropomyosin entwines around the actin. In the resting muscle,tropomyosin covers the binding sites on the actin subunits and prevents myosin cross bridge binding. 调节蛋白原肌球蛋白也是细丝的⼀部分。原肌球蛋白缠绕在肌动蛋白周围。在静息肌⾁中，原肌球蛋白覆盖肌动蛋白亚基上的结合位点并阻止肌球蛋白横桥结合。

Troponin 肌钙蛋白

To expose the binding sites for binding with myosin, the tropomyosin molecule must be moved aside. This is achieved by a third molecular complex called troponin. Troponin is attached and spaced periodically along the tropomyosin strand.

Calcium ions

Action potentials cause calcium ions to be released from the terminal cisternae, these bind to troponin. A conformational change occurs in the tropomyosin-troponin complex,which moves the tropomyosin strands away from the binding sites.

Cross-bridge cycle 过桥循环

1. attachment of the cross-bridge to a thin filament; 将横桥附着在细丝上；
2. movement of the cross-bridge, producing tension in the thin filament; 横桥移动，在细丝中产生张⼒；
3. detachment of the cross-bridge from the thin filament; 横桥与细丝脱离；
4. Energizing the cross-bridge so it can again attach to a thin filament and repeat the cycle. 给横桥通电，使其能够再次附着在细丝上并重复该循环。

1. Binding of Myosin to Actin: When a binding site on actin is exposed, an energised cross bridge can bind to it. The binding of myosin to actin brings about a conformational change in the cross bridge, resulting in the release of inorganic phosphate (Pi). 肌球蛋白与肌动蛋白的结合：当肌动蛋白上的结合位点暴露时，一个带电的横桥可以与其结合。肌球蛋白与肌动蛋白的结合会导致横桥的构象变化，从而释放无机磷酸盐 (Pi)。
2. The Power Stroke of the Cross Bridge: The myosin head pivots,pulling the thin filament inward toward the centre of the sarcomere: the power stroke. This conformational change releases ADP from its binding site. Chemical energy of ATP has been transformed into the mechanical energy of movement. 横桥的动力冲程：肌球蛋白头部旋转，将细丝向内拉向肌节中心：动力冲程。这种构象变化会将 ADP 从其结合位点释放出来。ATP 的化学能已转化为运动的机械能。
3. Disconnecting the Cross Bridge from Actin: In order to disconnect the cross bridge from actin, and relax the muscle an ATP molecule must bind to its site on the myosin cross bridge. 断开横桥与肌动蛋白的连接：为了断开横桥与肌动蛋白的连接，并放松肌肉，ATP 分子必须结合到肌球蛋白横桥上的位点。
4. Re-energising and positioning of the cross bridge: The release of the myosin cross bridge from actin triggers the hydrolysis of the ATP molecule into ADP and Pi. Energy is transferred from ATP to the myosin cross bridge, which returns to its high-energy conformation. 重新给横桥充电并定位：肌球蛋白横桥从肌动蛋白上释放会触发 ATP 分子水解为 ADP 和 Pi。能量从 ATP 转移到肌球蛋白横桥，肌球蛋白横桥恢复到高能构象。
5. Myosin Binding Sites on Actin are Hidden: Calcium is actively transported from the cytosol into the sarcoplasmic reticulum by ion pumps. As the calcium is removed,the troponin-tropomyosin complex again covers the binding sited on actin. 肌动蛋白上的肌球蛋白结合位点被隐藏：钙通过离子泵从胞质溶胶主动运输到肌浆网。随着钙被去除，肌钙蛋白-原肌球蛋白复合物再次覆盖肌动蛋白上的结合位点。

• Multiple Cross Bridge Cycles: Note that during a contraction,all cross bridges are neither bound nor disconnected at the same time 请注意，在收缩期间，所有横桥既不会同时结合也不会同时断开
• Multiple Myofilaments: Several myosin and actin filaments are interacting to demonstrate the sliding filament theory of muscle contraction. Notice that although the sarcomere shortens, the length of each myofilament does not change. However,the width of the H zone changes. 多条肌丝：多条肌球蛋白和肌动蛋白丝相互作用，证实了肌肉收缩的滑动丝理论。请注意，虽然肌节缩短，但每条肌丝的长度没有变化。然而，H 区的宽度发生了变化。

2.4.3 Mechanics of Single-Fiber Contraction

• The force exerted on an object by a contracting muscle is known as muscle tension and the force exerted on the muscle by an object (usually its weight) is the load. 收缩的肌⾁对物体施加的⼒称为肌⾁张⼒，物体（通常是其重量）对肌⾁施加的⼒称为负荷。
• When a muscle develops tension but does not shorten (or lengthen), the contraction is said to be isometric (constant length). 当肌⾁产生张⼒但不会缩短（或拉长）时，这种收缩被称为等长收缩（长度恒定）。
• A contraction in which the muscle shortens or lengthens while the load on the muscle remains constant, is said to be isotonic (constant tension). 当肌⾁负荷保持不变时，肌⾁缩短或伸长收缩，这种收缩被称为等张收缩（恒定张⼒）。
• Muscle tension and load are opposing forces. Whether or not force generation leads to fibre shortening depends on the relative magnitudes of the tension and the load. 肌⾁张⼒与负荷是相反的⼒量，⼒量的产生是否导致纤维缩短，取决于张⼒与负荷的相对大小。

2.4.3.1 Isometric and isotonic contractions

Isometric = same measurement i.e. constant length.
For example, when you exert increasing force say to try to pick up an immovable object. The muscle does not shorten but tension is produced. 例如，当你施加越来越大的⼒量，比如试图拿起一个不可移动的物体时，肌⾁不会缩短，但会产生张⼒。

Isotonic = same tone i.e. same tension.
The muscle shortens but the load against which it contracts is constant, e.g. when you pick up a weight. 肌⾁会缩短，但其收缩所承受的负荷是恒定的，例如当你举起重物时。

• During an isotonic contraction, the cross bridges bound to actin move to their angled positions, causing shortening of the sarcomeres. In contrast, during an isometric contraction, the bound cross bridges are unable to move the thin filaments because of the load on the muscle fibre, but they do exert a force on the thin filaments-isometric tension. 在等张收缩期间，与肌动蛋白结合的横桥会移动到其成⻆度的位置，从而导致肌节缩短。相反，在等长收缩期间，由于肌纤维上的负荷，结合的横桥⽆法移动细丝，但它们会对细丝施加⼒ ‑ 等长张⼒。
• During a lengthening contraction, the cross bridges are pulled backward toward the Z lines by the load while still bound to actin and exerting force. Thus, the chemical changes in the contractile proteins during each type of contraction are the same. 在伸长收缩过程中，横桥在负荷作⽤下向后拉向 Z 线，同时仍与肌动蛋白结合并施加⼒。因此，每种收缩过程中收缩蛋白的化学变
  化都是相同的。
• The end result is determined by the magnitude of the load on the muscle.

2.4.3.2 Twitch Contractions

• The mechanical response of a single muscle fibre to a single action potential is known as a twitch. 单个肌⾁纤维对单个动作电位的机械反应称为抽搐。
• Following the action potential, there is an interval of a few milliseconds, known as the latent period. 动作电位之后，有一个几毫秒的间隔，称为潜伏期。
• The time interval from the beginning of tension development at the end of the latent period to the peak tension is the contraction time. 从潜伏期末期开始出现张⼒到张⼒达到峰值的时间间隔为收缩时间。

The characteristics of an isotonic twitch depend upon the magnitude of the load being lifted: at heavier loads, the latent period is longer, and the velocity of shortening (distance shortened per unit of time), the duration of the twitch, and the distance shortened are all slower or shorter. 等张抽搐的特征取决于所举起的负荷的大小：负荷越大，潜伏期越长，而缩短速度（单位时间内缩短的距离）、抽搐持续时间和缩短的距离都越慢或越短。

The heavier the load, the longer it takes for the tension to increase to the value of the load, when shortening will begin. If the load on a fibre is increased, eventually a load is reached that the muscle is unable to lift, the velocity and distance of shortening will be zero, and the contraction will become completely isometric. 负荷越重，张⼒增加到负荷值所需的时间就越长，此时肌⾁就会开始缩短。如果纤维上的负荷增加，最终达到肌⾁⽆法举起的负荷，缩短的速度和距离将为零，收缩将完全等长。

2.4.3.3 Frequency-Tension Relation

• The increase in muscle tension from successive action potentials occurring during the phase of mechanical activity is known as summation.
• A maintained contraction in response to repetitive stimulation is known as a tetanus (tetanic contraction).
• At low stimulation frequencies, the tension may oscillate as the muscle fibre partially relaxes between stimuli, producing an unfused tetanus (incomplete tetanus). A fused tetanus (complete), with no oscillations, is produced at higher stimulation frequencies.
• Note: depolarisation is conducted along the T- tubules to the SR membrane, within a few milliseconds every sarcomere in a cell contracts simultaneously. 注意：去极化沿着 T 小管传导至 SR 膜，在几毫秒内，细胞中的每个肌节同时收缩。
• Action potentials cannot summate or fuse together because they are all-or-nothing as in nerve.
• However, the contractile responses can summate to form unfused (at around 10 Hz) and fused (at around 100 Hz) tetani.

2.4.3.4 Length-Tension Relation

• One can stretch a muscle fibre to various lengths and measure the magnitude of the active tension generated in response to stimulation at each length.
• The amount of active tension developed by a muscle fiber during contraction, and thus its strength, can be altered by changing the length of the fiber before contraction.
• The length at which the fibre develops the greatest isometric active tension is termed the optimal length. 纤维产生最大等长主动张⼒的长度称为最佳长度

2.4.3.5 Whole-Muscle Contraction

• The total tension a muscle can develop depends upon two factors:
  (1) the amount of tension developed by fibre, and (2) the number of fibres contracting at any time. 肌⾁所能产生的总张⼒取决于两个因素：（1）纤维产生的张⼒的大小，（2）随时收缩的纤维数量。
• The number of fibres contracting at any time depends on:
  (1) the number of fibres in each motor unit (motor unit size), and (2) the number of active motor units. 任何时候收缩的纤维数量取决于：（1）每个运动单位中的纤维数量（运动单位大小），以及（2）活跃运动单位的数量。
• The process of increasing the number of motor units that are active in a muscle at any given time is called recruitment. It is achieved by increasing the excitatory synaptic input to the motor neurons. The greater the number of active motor neurons, the more motor units recruited, and the greater the muscle tension. 增加肌⾁中某一时刻活跃的运动单位数量的过程称为募集。这是通过增加运动神经元的兴奋性突触输⼊来实现的。活跃的运动神经元数量越多，募集的运动单位就越多，肌⾁张⼒就越大。

Chapter 3 Blood Physiology

3.1 Plasma

General Functions of Blood

1. Transportation
   • O2 & CO2
   • nutrients and hormones
   • metabolic wastes
2. Regulation
   • extracellular fluid pH
   • body temperature
3. Protection
   • clotting mechanism 凝⾎机制
   • immune defence 免疫防御

Components of Blood

Haematocrit

• 55% plasma
• 45% cells
• 99% RBCs
• < 1% WBCs and platelets

• Percentage of blood occupied by cells
  • female normal range: 38 - 46% (average of 42%)
  • male normal range: 40 - 54% (average of 46%): testosterone
• Anemia
  • not enough RBCs or not enough hemoglobin
• Polycythemia
  • too many RBCs (over 65%)
  • dehydration, tissue hypoxia, blood doping in athletes

Physical Characteristics of Blood

• Thicker (more viscous) than water and flows more slowly than water
• Temperature of 100.4 degrees F
• pH 7.4 (7.35-7.45)
• 8 % of total body weight
• Blood volume
  • 5 to 6 liters in average male
  • 4 to 5 liters in average female
  • hormonal negative feedback systems maintain constant blood volume and osmotic pressure

Components of Plasma

• Water (>90％) and organic and inorganic substances
• Plasma proteins (65~85g/L)
  • Created in liver and confined to bloodstream
  • albumins: 40～48 g/L: maintain blood osmotic pressure
  • globulins: 15～30 g/L
    • α1-, α2-, β-, γ- globulins
    • Antibodies bind to antigens
  • fibrinogen: 2～4 g/L: For clotting
• Nutrients
• Metabolic wastes
• Hormones
• Mineral electrolytes

3.2 The Blood Cells

Haematopoiesis: process of blood cells formation is haematopoiesis or hemopoiesis

• Most blood cells types need to be continually replaced: die within hours, days or weeks
• In the embryo
  • occurs in yolk sac, liver, spleen, thymus, lymph nodes & red bone marrow 卵黄囊、肝脏、脾脏、胸腺、淋巴结和红骨髓中
• In adult
  • occurs only in red marrow of flat bones like sternum, ribs, skull & pelvis and ends of long bones 仅出现在胸骨、肋骨、头骨和骨盆等扁平骨的红骨髓以及⻓骨的末端

General Function of Blood Cells

• The blood cells are the erythrocytes and the leukocytes, and the cells fragments are the platelets (thrombocytes).
• More than 99% of blood cells are erythrocytes, which transport gas.
• The leukocytes protect against infection and cancer, and the platelets function in blood clotting.

3.2.1 Physiology of Erythrocyte

• biconcave discs: 7 ~ 8 μm,
• lack a nucleus and can’t devide
• high Hb concentrations
• lifespan: 80-120 days

3.2.1.1 Physiological characteristic 生理特征

• Permeability of membrane 膜通透性
  • Free to gas, like O2 , CO2 , NO (Isosmotic ≠ Isotonic)
• Deformability 可变形性
  • Behaving as elastic bodies, erythrocytes respond to applied pressure (ie, decrease in vessel diameter) by extensive changes in their shape followed by a reversal when the deforming force is removed. 细胞是⼀种弹性体，当受到压力（即⾎管直径减⼩）时，其形状会发生⼤幅度变化，而当变形力消失后，形状又会逆转
• Suspension stability 悬挂稳定性
  • greater surface area/volume
  • negative charge of RBC membrane 红细胞膜带负电荷

3.2.1.2 Erythrocytes Osmotic Fragility

Osmotic fragility of RBCs is defined as the ease with which the cells burst in hypotonic solutions and is expressed in terms of the concentration of the saline solution in which the cells are haemolyzed. 红细胞的渗透脆性定义为细胞在低渗溶液中破裂的难易程度，以细胞溶⾎的盐溶液浓度来表⽰

Hereditary spherocytosis and thalassemia cause red blood cells to be more fragile than normal, might leading to haemolytic anaemia (anemia AmE).

3.2.1.3 Erythrocyte Sedimentation Rate (ESR) 红细胞沉降率

ESR is a blood test that can show inflammatory activity in the body.

3.2.1.4 Erythrocyte formation 红细胞形成

• The production of erythrocytes : red bone marrow 红骨髓
• Key factor for production: iron and vitamins like folic acid and B12

3.2.1.5 Recycling of haemoglobin ⾎红蛋白的回收利⽤

• In liver or spleen 肝脏或脾脏
  • globin portion broken down into amino acids & recycled 珠蛋白部分分解成氨基酸并回收
  • haem (heme AmE) portion split into iron ($Fe^{3+}$) and biliverdin (green pigment) ⾎红素部分分解为铁（$Fe^{3+}$）和胆绿素（绿色色素）

3.2.1.6 Regulation of Erythrocyte Production (erythropoiesis) 红细胞生成的调节（红细胞生成）

• Erythropoietin (EPO) produced by Kidneys (connective-tissue cells in the kidneys, the liver also
  secretes this hormone, but to a much lesser extent). 促红细胞生成素 (EPO) 由肾脏产生（肾脏、肝脏中的结缔组织细胞也会分泌这种激素，但程度要⼩得多）
• EPO acts on the bone marrow to stimulate the proliferation of erythrocyte progenitor cells and their differentiation into mature erythrocytes. EPO作⽤于骨髓，刺激红细胞祖细胞增殖并分化为成熟红细胞
• Increased EPO responds to tissue hypoxia. EPO 增加可应对组织缺氧
• Testosterone also stimulates the release of erythropoietin. 睾酮还能刺激促红细胞生成素的释放

3.2.1.7 Anaemia 贫⾎

Decrease in the absolute quantity of hemoglobin.

• Dietary deficiencies of iron (iron-deficiency anemia), vitamin B12, or folic acid
• Bone marrow failure due to toxic drugs or cancer
• Blood loss from the body (hemorrhage)
• Inadequate secretion of erythropoietin in kidney disease
• Excessive destruction of erythrocytes(for example,sickle-cell disease)

3.2.2 Physiology of Leukocytes

• All WBCs (leukocytes) have a nucleus and no haemoglobin 所有白细胞 (WBC) 都有细胞核，没有⾎红蛋白
• Granular or agranular classification based on presence of cytoplasmic granules made visible by staining 根据染色后可⻅的细胞质颗粒，进行颗粒状或⽆颗粒状分类
  • granulocytes are neutrophils, eosinophils or basophils 粒细胞是中性粒细胞、嗜酸性粒细胞或嗜碱性粒细胞
  • agranulocytes are monocytes or lymphocytes ⽆粒细胞是单核细胞或淋巴细胞

3.2.2.1 Neutrophil

• Fastest response of all WBC to bacteria 所有白细胞对细菌反应最快的
• Direct actions against bacteria
  • release lysozymes which destroy / digest bacteria 释放溶菌酶来破坏/消化细菌
  • release defensin proteins that act like antibiotics & poke holes in bacterial cell walls destroying them 释放出像抗生素⼀样的防御素蛋白，在细菌细胞壁上戳洞，摧毁它们
  • release strong oxidants (bleach-like, strong chemicals) that destroy bacteria 释放强氧化剂（类似漂白剂的强力化学物质），杀死细菌

3.2.2.2 Monocyte

• Take longer to get to site of infection, but arrive in larger numbers 到达感染部位需要更⻓时间，但到达的人数更多
• Become wandering macrophages, once they leave the capillaries ⼀旦离开⽑细⾎管，就变成游走的巨噬细胞
• Destroy microbes and clean up dead tissue following an infection

3.2.2.3 Lymphocyte

• B cells
  • destroy bacteria and their toxins
  • turn into plasma cells that produces antibodies
• T cells
  • attack viruses, fungi, transplanted organs, cancer cells & some bacteria
• Natural killer cells
  • attack many different microbes & some tumor cells
  • destroy foreign invaders by direct attack

3.2.3 Physiology of Platelets (Thrombocytes)

Counts and Morphology

• Disc-shaped, 2 - 4 micron cell fragment
• with no nucleus
• Normal platelet count: 150,000-400,000/drop of blood

Life span

• Short life span (5 to 9 days in bloodstream)
  • formed in bone marrow
  • few days in circulating blood
  • aged ones removed by fixed macrophages in liver and spleen

Function

• Play important roles in hemostasis
  • Direct adhesion
  • Platelet-derived growth factor (PDGF)
    • cause proliferation of vascular endothelial cells, smooth muscle & fibroblasts
    to repair damaged vessels

3.3 Haemostasis: The Prevention of Blood Loss

Haemostasis (Hemostasis AmE)

• Stoppage of bleeding in a quick & localized fashion when blood vessels are damaged
• Prevents hemorrhage (loss of a large amount of blood)
• Methods utilized
  • vascular spasm ⾎管收缩
  • platelet plug formation ⾎⼩板栓塞形成
  • blood clotting (coagulation = formation of fibrin threads) ⾎液凝固（凝固 = 纤维蛋白丝形成）

3.3.1 Vascular Spasm

• Damage to blood vessel produces stimulates pain receptors ⾎管损伤会刺激疼痛感受器
• Reflex contraction of smooth muscle of small blood vessels ⼩⾎管平滑肌反射性收缩
• Can reduce blood loss for several hours until other mechanisms can take over
• Only for small blood vessel or arteriole 仅适⽤于⼩⾎管或⼩动脉

3.3.2 Platelet Plug Formation

• Adhesion to collagen: vWF
• Release: a variety of chemical agents via secretory vesicles 通过分泌囊泡释放各种化学物质
  • Alpha-granules: clotting factors, PDGF
  • Dense granules: ADP, ATP, $Ca^{2+}$, serotonin, fibrin-stabilizing factor, & enzymes that produce thromboxane A2. ADP、ATP、Ca2+、⾎清素、纤维蛋白稳定因子和产生⾎栓素 A2 的酶
• Aggregation: new platelets adhered to the old ones due to the platelet release reaction

• Why is the platelet plug limited to damage endothelium?
  • Inhibitory factors for platelet aggregation are released in intact endothelium. 完整的内皮会释放⾎⼩板聚集的抑制因子

3.3.3 Blood Coagulation: Clot Formation

• Blood drawn from the body thickens into a gel 从⾝体抽出的⾎液变稠变成凝胶
  • gel separates into liquid (serum) and a clot of insoluble fibres (fibrin) in which the cells are trapped 凝胶分离成液体（⾎清）和⼀团不溶性纤维（纤维蛋白），细胞被困在其中
• If clotting occurs in an unbroken vessel is called a thrombosis 如果未破裂的⾎管中发生凝⾎，则称为⾎栓形成
• Substances required for clotting are $Ca^{2+}$, enzymes synthesized by liver cells and substances released by platelets or damaged tissues
• Clotting is a cascade of reactions in which each clotting factor activates the next in a fixed sequence resulting in the formation of fibrin threads 凝⾎是⼀系列反应，其中每个凝⾎因子按固定顺序激活下⼀个凝⾎因子，导致纤维蛋白丝的形成
  • prothrombinase & $Ca^{2+}$ convert prothrombin into thrombin 凝⾎酶原酶和$Ca^{2+}$将凝⾎酶原转化为凝⾎酶
  • thrombin converts fibrinogen into fibrin threads 凝⾎酶将纤维蛋白原转化为纤维蛋白丝

3.3.3.1 Clotting factors

• There are many clotting factors in blood.
• The clotting factors work one after the other. At the end of the chain, bleeding stops.
• If one is missing or does not work, clots will not form properly and bleeding will continue. 如果缺少⼀个或者不起作⽤，⾎凝块就⽆法正常形成，出⾎就会持续

3.3.3.2 Stage of blood coagulation

1. Prothrombinase is formed by either the intrinsic or extrinsic pathway 凝⾎酶原酶由内在或外在途径形成
2. Prothrombin is converted to thrombin 凝⾎酶原转化为凝⾎酶
3. Final common pathway produces fibrin threads 最后的共同通路产生纤维蛋白丝

Extrinsic Pathway 外在途径

• Damaged tissues leak tissue factor (thromboplastin) into bloodstream 受损组织泄漏组织因子（凝⾎活酶）进入⾎液
• Prothrombinase forms in seconds 凝⾎酶原酶在数秒内形成
• In the presence of $Ca^{2+}$, clotting factor X combines with V to form prothrombinase ，凝⾎因子 X 与 V 结合形成凝⾎酶原酶

Intrinsic Pathway 内在途径

• Activation occurs
  • endothelium is damaged & platelets come in contact with collagen of blood vessel wall 内皮受损，⾎⼩板与⾎管壁胶原蛋白接触
  • platelets damaged & release phospholipids ⾎⼩板受损并释放磷脂
• Requires several minutes for reaction to occur 反应需要⼏分钟才能发生
• Substances involved: $Ca^{2+}$ and clotting factors XII, X and V

3.3.3.3 Role of Vitamin K in Clotting

• Normal clotting requires adequate vitamin K 正常凝⾎需要⾜够的维生素 K
  • fat soluble vitamin absorbed if lipids are present 脂溶性维生素在脂质存在的情况下被吸收
  • absorption slowed if bile release is insufficient 如果胆汁释放不⾜，吸收就会减慢
• Required for synthesis of 4 clotting factors by hepatocytes 肝细胞合成 4 种凝⾎因子所需
  • factors II (prothrombin), VII, IX and X
• Produced by bacteria in large intestine 由⼤肠中的细菌产生

3.3.4 Anticlotting system

• tissue factor pathway inhibitor (TFPI) 组织因子途径抑制剂 (TFPI) 抑制 Xa 因子
  • Inactivates factor Xa
• Thrombomodulin receptor ⾎栓调节蛋白受体 抑制 Va 因子和 XIIIa 因子
  • Inactivates factor Va and XIIIa
• antithrombin III 抗凝⾎酶III 抑制凝⾎酶和其他因子
  • Inactivates thrombin and other factors

3.3.4.1 Fibrinolytic system 纤溶系统

The fibrinolytic (or thrombolytic) system is the principal effector of clot removal. 纤维蛋白溶解（或⾎栓溶解）系统是清除⾎凝块的主要效应器

• Fibrinolytic system dissolves small, inappropriate clots & clots at a site of a completed repair 纤维蛋白溶解系统溶解⼩的、不适当的⾎凝块和已完成修复部位的⾎凝块
  • fibrinolysis is dissolution of a clot 纤维蛋白溶解是⾎凝块的溶解
• Inactive plasminogen is incorporated into the clot ⽆活性的纤溶酶原被掺入⾎凝块中
  • activation occurs because of factor XII and thrombin 由于因子 XII 和凝⾎酶而发生激活
  • plasminogen becomes plasmin (fibrinolysin) which digests fibrin threads 纤溶酶原变成纤溶酶（纤维蛋白溶酶），可消化纤维蛋白丝

3.3.4.2 Anticlotting Drugs

• Anticoagulants suppress or prevent blood clotting 抗凝剂抑制或预防⾎液凝固
  • heparin: administered during haemodialysis (hemodialysis AmE) and surgery 肝素：⾎液透析和手术期间使⽤
  • warfarin (Coumadin): antagonist to vitamin K so blocks synthesis of clotting factors, slower than heparin 华法林（Coumadin）：维生素 K 拮抗剂，可阻止凝⾎因子的合成，速度比肝素慢
  • stored blood in blood banks treated with citrate phosphate dextrose (CPD) that removes $Ca^{2+}$ ⾎库中储存的⾎液经过柠檬酸磷酸葡萄糖 (CPD) 处理
• Thrombolytic agents are injected to dissolve clots 注射溶栓剂来溶解⾎栓
  • directly or indirectly activate plasminogen 直接或间接激活纤溶酶原
  • streptokinase or tissue plasminogen activator (t-PA) 链激酶或组织纤溶酶原激活剂 (t‑PA)

3.4 Blood Groups and Blood Transfusion

3.4.1 ABO Blood Groups

• Based on 2 glycolipid iso-antigens called A and B found on the surface of
  RBCs
  • display only antigen A – blood type A
  • display only antigen B – blood type B
  • display both antigens A & B – blood type AB
  • display neither antigen – blood type O
• Plasma contains isoantibodies or agglutinins to the A or B antigens not found in your blood
  • anti-A antibody reacts with antigen A
  • anti-B antibody reacts with antigen B

RBC surfaces are marked by genetically determined glycoproteins & glycolipids

• agglutinogens or iso-antigens
• distinguishes at least 24 different blood groups
  • ABO, Rh, Lewis, Kell, Kidd and Duffy systems

3.4.2 Typing and Cross-Matching Blood

• Mixing of incompatible blood causes agglutination (visible clumping)
  • formation of antigen-antibody complex that sticks cells together
  • not the same as blood clotting
• Typing involves testing blood with known antisera that contain antibodies A, B or Rh+
• Cross-matching is to test by mixing donor cells with recipient’s serum
• Screening is to test recipient’s serum against known RBC’s having known antigens

Transfusion and Transfusion Reactions

• Transfer of whole blood, cells or plasma into the bloodstream of recipient

  • used to treat anaemia or severe blood loss

• Incompatible blood transfusions

  • antigen-antibody complexes form between plasma antibodies & “foreign proteins” on donated RBC’s (agglutination)
  • donated RBCs become leaky (complement proteins) & burst
  • loose haemoglobin causes kidney damage

• Problems caused by incompatibility between donor’s cells and recipient’s plasma

• Donor plasma is too diluted to cause problems

Chapter 5 Respiratory Physiology

5.1 Pulmonary Ventilation and Lung Mechanics

5.1.1 Organization of the Respiratory System

5.1.1.1 The Respiratory Tract 呼吸道

• Consists of a conducting portion
  • From nasal cavity to terminal bronchioles
• Consists of a respiratory portion
  • The respiratory bronchioles and alveoli

5.1.1.2 Conducting zone 传导区

• The conducting zone extends from the top of the trachea to the beginning of the respiratory bronchioles; it contains no alveoli and there is no gas exchange with the blood. 传导区从⽓管顶部延伸至呼吸性细⽀⽓管的起始处；它不包含肺泡，并且不与⾎液进行⽓体交换
• Trachea, Bronchi, larger bronchioles-allows air flow
• Have cartilage rings - robust will not collapse 有软骨环‑坚固不会塌陷
• Cells: Ciliated epithelium; Goblet cells; Smooth muscle cells 细胞：纤⽑上皮；杯状细胞；平滑肌细胞

5.1.1.3 Respiratory zone 呼吸区

• The respiratory zone, which extends from the respiratory bronchioles down, contains alveoli and is the region where gases exchange with the blood. 呼吸区从呼吸性细⽀⽓管向下延伸，包含肺泡，是⽓体与⾎液交换的区域
• Cells: Type I, Type II
• For gases to exchange efficiently:
  • Alveoli walls must be very thin (<1 μm)
  • Surface area must be very great (about 35 times the surface area of the body)
• Most of the air-facing surfaces of the wall are lined by a continuous layer, one cell thick, of flat epithelial cells termed type I alveolar cells. ⼤部分⾯向空⽓的壁表⾯都覆盖有⼀层连续的扁平上皮细胞，厚度只有⼀个细胞，称为 I 型肺泡细胞
• Interspersed between these cells are thicker specialized cells termed type II alveolar cells that produce a detergent-like substance, surfactant. 这些细胞之间散布着更厚的特殊细胞，称为 II 型肺泡细胞，产生⼀种类似洗涤剂的物质：表⾯活性剂。
• The respiratory membrane is composed of 6 layers:
  1. a layer of fluid containing surfactant that lines the alveolus and reduces the surface tension; ⼀层含有表⾯活性剂的液体，排列在肺泡上，减少表⾯紧张;
  2. the alveolar epithelium; 肺泡上皮；
  3. an epithelial basement membrane; 上皮基底膜；
  4. a thin interstitial space between the alveolar epithelium and the capillary membrane; 肺泡上皮和⽑细⾎管膜之间的薄间质空间；
  5. a capillary basement membrane; ⽑细⾎管基底膜；
  6. the capillary endothelial membrane. ⽑细⾎管内皮膜

5.1.1.4 Alveoli 肺泡

• Are air-filled pockets within the lungs
• Where all gas exchange takes place
• Inspiration (inhalation) is the movement of air from the external environment through the airways into the alveoli during breathing.
• Expiration (exhalation) is movement in the opposite direction. An inspiration and expiration constitute a respiratory cycle.

5.1.1.5 Relation of the Lungs to the Thoracic (Chest) Wall

The Pleura 胸膜

• Consists of two layers:
  • Parietal pleura
  • Visceral pleura
• Pleural fluid
  • Lubricates space between two layers
  • the total volume is only a few milliliters

5.1.2 Ventilation and Lung mechanics

5.1.2.1 Ventilation

• External respiration - the exchange of gases between the body and the environment. ⾝体与环境之间的⽓体交换
• Gas transport - O2 is transported from lungs to the tissues and CO2 is transported in the opposite direction by blood circulation. O2 从肺部运输到组织，CO2 通过⾎液循环以相反的方向运输。
• Gas diffusion – gas is transported over short distances of a few micrometres—e.g., through cell membranes and other physiological barriers. ⽓体在⼏微米的短距离内运输；例如，通过细胞膜和其他生理屏障
• Internal respiration - the exchange of gas occurs between the blood and cells of tissues and O2 utilization in the cells. ⾎液和组织细胞之间发生⽓体交换，细胞中利⽤ O2
• Ventilation - the exchange of gas between the atmosphere and alveoli. 􀀀⼤⽓与肺泡之间的⽓体交换

Pulmonary Ventilation
• Is the physical movement of air in and out of respiratory tract 是空⽓进出呼吸道的物理运动
• Provides alveolar ventilation
$$
𝐹 = (𝑃_{𝑎𝑙𝑣} − 𝑃_{𝑎𝑡𝑚})/𝑅
$$

$F$: air flow
$P_{alv}$: alveolar pressure
$P_{atm}$: atmospheric pressure
$R$: resistance

• During ventilation, air moves into and out of the lungs because the alveolar pressure is alternately made less than and greater than atmospheric pressure.
• The lungs are passive elastic structures—like balloons—and their volume, therefore, depends upon:
  1. the difference in pressure—termed the transpulmonary pressure—between the inside and the outside of the lungs; 肺内和肺外的压力差，称为跨肺压以及肺部外部；
  2. how stretchable the lungs are. 肺部的伸展性如何

$$
Transpulmonary,Pressure=P_{alv}-P_{ip}
$$

Transpulmonary pressure

5.1.2.2 The Respiratory Muscles

• The diaphragm 横膈膜
• External intercostal muscles of the ribs 肋骨外肋间肌
• Accessory respiratory muscles:
  • activated when respiration increases significantly 辅助呼吸肌：当呼吸显著增加时激活

Muscles of Active Exhalation 主动呼⽓的肌⾁

• Internal intercostal and transversus thoracis muscles
  • Depress the ribs 压低肋骨
• Abdominal muscles
  • Compress the abdomen 挤压腹部
  • Force diaphragm upward 迫使横膈膜向上

Lung Compliance 肺顺应性

• An indicator of expandability
• Low compliance requires greater force
• High compliance requires less force

Factors That Affect Compliance

• Connective tissue structure of the lungs 肺的结缔组织结构
• Level of surfactant production 表⾯活性剂生产水平
• Mobility of the thoracic cage 胸廓的活动性

5.1.2.3 Inspiration and Expiration

Inhalation: Always active

Exhalation: Active or passive

How does airway resistance change? ⽓道阻力如何变化？

• Airway resistance to airflow is normally very small ⽓道对⽓流的阻力通常很⼩
• Physical factor: transpulmonary pressure and lateral traction 物理因素：跨肺压和侧向牵引
• Neuroendocrine and paracrine factors: epinephrine, leukotrienes 神经内分泌和旁分泌因子：肾上腺素、白三烯

5.1.3 Lung Volumes and Capacities

• Tidal volume (TV): the volume of air entering the lungs during a single inspiration. The tidal volume during normal quiet breathing is termed the resting tidal volume and is approximately 500ml. 单次吸⽓时进入肺部的空⽓量。正常安静呼吸时的潮⽓量称为静息潮⽓
• Inspiratory reserve volume (IRV): the maximal amount of air that can be increased above TV during deepest inspiration (3000ml). 最深吸⽓时可增加至 TV 以上的最⼤空⽓量
• Expiratory reserve volume (ERV): maximal extra volume of air that can be expired by forceful expiration after the end of a normal tidal expiration (900-1200ml) 正常潮⽓量结束后⽤力呼⽓所能呼出的最⼤额外空⽓量
• Residual volume (RV): after a maximal active expiration, approximately 1200ml of air still remains in the lungs. 最⼤主动呼⽓后，肺内仍残留约1200ml空⽓
• Vital capacity (VC): the maximal volume of air that a person can expire after a maximal inspiration. ⼀个人最⼤程度吸⽓后能够呼出的最⼤空⽓量
• Inspiratory capacity (IC): is equal to the tidal volume plus the inspiratory reserve volume. 等于潮⽓量加上补吸⽓量
• Functional residual capacity (FRC): After expiration of a resting tidal volume, the lungs still contain a very large volume of air. 静息潮⽓量呼出后，肺部仍然含有⼤量空⽓
• Total lung capacity (TLC): Maximum amount of air that can be inhaled after a normal tidal expiration. 正常潮⽓呼⽓后可吸入的最⼤空⽓量
• Forced expiratory volume in 1 sec (FEV1): In 1s, the person takes a maximal inspiration
  and then exhales maximally as fast as possible. 在1秒内，人以最⼤程度吸⽓，然后尽可能快地最⼤程度呼⽓

5.1.4 Dead Space and Alveolar Ventilation

5.1.4.1 Minute Ventilation

The total ventilation per minute—the minute ventilation ($\dot{V}_E$)—is equal to the tidal volume multiplied by the respiratory rate as shown in equation 13–6. (The dot above the letter $V$ indicates per minute.) 每分钟总通⽓量（分钟通⽓量）等于潮⽓量乘以呼吸频率

5.1.4.2 Dead Space

Dead space is the volume of inspired air that does not take part in gas exchange. There are two reasons why this occurs. 死腔是指吸入的空⽓中未参与⽓体交换的部分

• The first is due to the anatomy of the airways themselves. Anatomic dead space: Part of atmospheric air entering the respiratory system during each inspiration never reaches the alveoli but is merely moved in and out of the airways. 第⼀是⽓道本⾝的解剖结构。解剖死腔：每次吸⽓时进入呼吸系统的部分⼤⽓空⽓从未到达肺泡，而只是进出⽓道。
• The second component of dead space occurs because some fresh inspired air is not used for gas exchange with the blood even though it reaches the alveoli. This is because some alveoli may, for various reasons, have little or no blood supply. This volume of air is known as alveolar dead space. It is quite small in healthy persons but may be very large with lung disease. As we shall see, local mechanisms that match air and blood flows minimize the alveolar dead space. 死腔的第二个组成部分是因为一些新鲜吸入的空气即使到达肺泡也没有用于与血液进行气体交换。这是因为一些肺泡可能由于各种原因很少或没有血液供应。该体积的空气称为肺泡死腔。它在健康人中相当小，但在患有肺部疾病时可能非常大。正如我们将看到的，匹配空气和血液流动的局部机制最大限度地减少了肺泡死腔。

The sum of the anatomical and alveolar dead spaces is known as the physiological dead space. 解剖学死腔和肺泡死腔的总和称为生理死腔。

5.1.4.3 Alveolar Ventilation

The total volume of fresh air entering the alveoli per minute is called the alveolar ventilation ($\dot{V}_A$). 每分钟进入肺泡的新鲜空⽓总量称为肺泡通⽓量。

5.2 Exchange of Gases in Alveoli and Tissues

5.2.1 Foundational Principles of Gas Exchange: Diffusion of Gases

5.2.1.1 Partial Pressure of Gases

• A mixture of gases exert a pressure
• An individual gas exerts a partial pressure in the mixture
• Each gas contributes to the total pressure (Dalton’s law)

5.2.1.2 Diffusion of Gases in Liquids

Henry’s Law

• When gas under pressure comes in contact with liquid
  • Gas dissolves in liquid until equilibrium is reached
• At a given temperature
  • Amount of a gas in solution is proportional to partial pressure of that gas

Gas Content

• The actual amount of a gas in solution (at given partial pressure and temperature) depends on the solubility of that gas in that particular liquid

Solubility in Body Fluids

• CO2 is very soluble
• O2 is less soluble
• N2 has very low solubility

5.2.2 Exchange Between Alveoli and Blood

Efficiency of Gas Exchange Due to:

• Substantial differences in partial pressure across the respiratory membrane 呼吸膜两侧分压存在显著差异
• Distances involved in gas exchange are short ⽓体交换距离较短
• O2 and CO2 are lipid soluble O2 和 CO2 可溶于脂溶性
• Total surface area is large 总表⾯积⼤
• Blood flow and airflow are coordinated ⾎流和⽓流协调

Ventilation versus perfusion 通⽓与灌注

• Matching the blood flow to the parts of the lung where the oxygen is 将⾎流与肺部氧⽓充⾜的部位相匹配
• Ventilation / perfusion ratio 通⽓/灌注比
• Not equal across the lung (because of where the heart is). Can change due to metabolism 肺部不同（因为⼼脏的位置不同），可能因新陈代谢而改变
• Can change with disease-asthma, pulmonary hypertension 可能因哮喘、肺动脉⾼压等疾病而改变

5.3 Transport of Oxygen and Carbon Dioxide in the Blood

5.3.1 Transport of Oxygen in the Blood

The oxygen is present in two forms:

1. dissolved in the plasma and erythrocyte cytosol 溶解于⾎浆和红细胞胞质中
2. reversibly combined with haemoglobin molecules in the erythrocytes 与红细胞中的⾎红蛋白分子可逆地结合

As predicted by Henry’s law, the amount of oxygen dissolved in blood is directly proportional to the $P_{O_2}$ of the blood. 根据亨利定律预测，血液中溶解的氧气量与血液中的 $P_{O_2}$ 成正比。

5.3.1.1 Haemoglobin

Each hemoglobin molecule is a protein made up of four subunits bound together. Each subunit consists of a molecular group known as heme and a polypeptide attached to the heme. The four polypeptides of a hemoglobin molecule are collectively called globin. Each of the four heme groups in a hemoglobin molecule (Figure 13.25) contains one atom of iron ($Fe^{2+}$), to which molecular oxygen binds. Because each iron atom shown in Figure 13.25 can bind one molecule of oxygen, a single hemoglobin molecule can bind four oxygen molecules (see Figure 2.19 for the quaternary structure of hemoglobin). 每个血红蛋白分子都是由四个结合在一起的亚基组成的蛋白质。每个亚基由称为血红素的分子组和附着在血红素上的多肽组成。血红蛋白分子的四种多肽统称为珠蛋白。血红蛋白分子中的四个血红素基团（图 13.25）中的每一个都含有一个铁原子 ($Fe^{2+}$)，分子氧与其结合。因为图13.25所示的每个铁原子可以结合一个氧分子，所以单个血红蛋白分子可以结合四个氧分子（血红蛋白的四级结构见图2.19）。

deoxyhemoglobin - oxyhemoglobin

5.3.1.2 Haemoglobin Saturation ⾎红蛋白饱和度

The percentage of haem units in a haemoglobin molecule

5.3.1.2.1 Effect of partial pressure of O2

Oxygen–Haemoglobin Saturation Curve

• Is a curve rather than a straight line
  • Because Hb changes shape each time a molecule of O2 is bound
• Each O2 bound makes next O2 binding easier
• Allows Hb to bind O2 when O2 levels are low

Oxygen Reserves

• O2 diffuses
  • From peripheral capillaries (high $P_{O_2}$)
  • Into interstitial fluid (low $P_{O_2}$)
• Amount of O2 released depends on interstitial $P_{O_2}$
• Up to 3/4 may be reserved by RBCs 最多 3/4 可以由 RBC 保留

5.3.1.2.2 Effect of Carbon Monoxide

• CO from burning fuels
  • Binds strongly to hemoglobin
  • Takes the place of O2
  • Can result in carbon monoxide poisoning

5.3.1.2.3 Effect of pH and temperature (normal pH 7.4, 37℃)

• When pH drops or temperature rises
  • More oxygen is released 当 pH 值下降或温度升⾼时 释放更多氧气
• When pH rises or temperature drops
  • Less oxygen is released 当 pH 值上升或温度下降时 释放的氧气减少

5.3.1.2.4 The Bohr Effect

• Is the effect of pH on hemoglobin-saturation curve
• Caused by CO2
  • CO2 diffuses into RBC
  • An enzyme, called carbonic anhydrase, catalyzes reaction with H2O ⼀种称为碳酸酐酶的酶催化与 H2O 的反应
  • Produces carbonic acid (H2CO3)
• Carbonic acid (H2CO3)
  • Dissociates into hydrogen ion (H^+^) and bicarbonate ion (HCO3^-^)
• Hydrogen ions diffuse out of RBC, lowering pH 氢离子从红细胞中扩散出来，降低 pH 值

5.3.1.2.5 Effect of 2,3-bisphosphoglycerate (DPG) 2,3‑双磷酸⽢油酸

• RBCs generate ATP by glycolysis 红细胞通过糖酵解产生 ATP
  • Forming lactic acid and DPG 形成乳酸和DPG
• DPG directly affects O2 binding and release
  • More DPG, more oxygen released DPG 越多，释放的氧气越多

5.3.2 Transport of Carbon Dioxide in Blood

• Physically dissolved in the blood (10%) 物理溶解
• Bound to haemoglobin (25-30%) 与⾎红蛋白结合
• bicarbonate (60-65%) 碳酸氢盐

Bicarbonate Ions

• Move into plasma by an exchange mechanism (the chloride shift) that takes in Cl^-^ ions without using ATP 过交换机制（氯离子转移）进⼊⾎浆，⽆需使⽤ ATP 即可吸收 Cl^‑^ 离子

Hydrogen Ions

• Deoxyhaemoglobin has a much greater affinity for H^+^ 脱氧⾎红蛋白对 H^+^ 的亲和⼒更强

5.4 Control of Respiration

5.4.1 Neural Generation of Rhythmic Breathing

The respiratory centres: Three pairs of nuclei in the reticular formation of medulla oblongata and pons 呼吸中枢：延髓和脑桥⽹状结构中的三对核

Respiratory rhythmicity centres of the medulla oblongata: set the pace of respiration 延髓的呼吸节律中⼼：设定呼吸的节奏

• Dorsal respiratory group (DRG): The neurons of the dorsal respiratory group (DRG) primarily fire during inspiration and have input to the spinal motor neurons that activate respiratory muscles involved in inspiration—the diaphragm and inspiratory intercostal muscles. The primary inspiratory muscle at rest is the diaphragm, which is innervated by the phrenic nerves. 背侧呼吸群 (DRG) 的神经元主要放电吸气过程中，并输入脊髓运动神经元，激活参与吸气的呼吸肌——膈肌和吸气肋间肌。静止时的主要吸气肌是膈肌，由膈神经支配。
  • Inspiratory center
  • Functions in quiet and forced breathing
• Ventral respiratory group (VRG): The ventral respiratory group (VRG) is the other main complex of neurons in the medullary respiratory centre. The respiratory rhythm generator is located in the pre-Bötzinger complex of neurons in the upper part of the VRG. 腹侧呼吸群（VRG）是延髓呼吸中枢的另一个主要神经元复合体。呼吸节律发生器位于 VRG 上部神经元的前 Bötzinger 复合体中。
  • Inspiratory and expiratory center
  • Functions only in forced breathing

During increases in breathing, the inspiratory and expiratory motor neurons and muscles are not activated at the same time but, rather, alternate in function. 在呼吸增加的过程中，吸气和呼气运动神经元和肌⾁不会同时激活，而是交替发挥作⽤

• The Apneustic and Pneumotaxic Centres of the Pons 脑桥的呼吸暂停和呼吸调节中⼼
  • Paired nuclei that adjust output of respiratory rhythmicity centres 调节呼吸节律中⼼输出的成对核
  • Regulating respiratory rate and depth of respiration 调节呼吸频率和呼吸深度
• Apneustic Centre 呼吸暂停中⼼
  • Provides continuous stimulation to its DRG centre
• Pneumotaxic Centres 呼吸调节中⼼
  • Inhibit the apneustic centres 抑制呼吸暂停中枢
  • Promote passive or active exhalation 促进被动或主动呼气

The Hering-Breuer Reflexes

5.4.2 Chemoreceptor Reflex of Breathing

5.4.2.1 Chemoreceptors

Peripheral chemoreceptor 外周化学感受器

• Carotid body 颈动脉体
  • The glossopharyngeal nerve (Cranial nerve IX)
  • Stimulated by changes in blood pH or $P_{O_2}$
• Aortic body 主动脉体
  • The vagus nerve (Cranial nerve X)
  • Stimulated by changes in blood pH or $P_{O_2}$

The peripheral chemoreceptors, located high in the neck at the bifurcation of the common carotid arteries and in the thorax on the arch of the aorta (Figure 13.33), are called the carotid bodies and aortic bodies, respectively. In both locations, they are quite close to, but distinct from, the arterial baroreceptors and are in intimate contact with the arterial blood. The carotid bodies, in particular, are strategically located to monitor oxygen supply to the brain. 外周化学感受器位于颈部高位颈总动脉分叉处和胸腔主动脉弓处（图 13.33），分别称为颈动脉体和主动脉体。在这两个位置，它们都非常接近但又不同于动脉压力感受器，并且与动脉血液密切接触。特别是颈动脉体的位置非常重要，可以监测大脑的氧气供应。

Central chemoreceptor 中枢化学感受器

• Respiratory centre of medulla oblongata 延髓呼吸中枢
  • ventrolateral surface
• monitor cerebrospinal fluid 监测脑脊液
  • respond to pH and $P_{CO_2}$ change

The central chemoreceptors are located in the medulla and, like the peripheral chemoreceptors, provide excitatory synaptic input to the medullary inspiratory neurons. They are stimulated by an increase in the H^+^ concentration of the brain’s extracellular fluid. As we will see later, such changes result mainly from changes in blood $P_{CO_2}$. 中枢化学感受器位于髓质中，与外周化学感受器一样，为髓质吸气神经元提供兴奋性突触输入。它们受到大脑细胞外液 H^+^ 浓度增加的刺激。正如我们稍后将看到的，这种变化主要是由血液 $P_{CO_2}$ 的变化引起的。

5.4.2.2 Control of ventilation by $P_{O_2}$​

5.4.2.3 Control of ventilation by $P_{CO_2}$

5.4.2.4 Control Ventilation by $H^+$

Chapter 4 Cardiovascular Physiology

The Cardiovascular system (CVS) serves to provide rapid transport of nutrients to the tissues in the body and allow rapid removal of waste products.

Main functions of CVS

1. Rapid transport of nutrients (oxygen, amino acids, glucose, fatty acids, water, etc.) 快速运输营养物质（氧气、氨基酸、葡萄糖、脂肪酸、⽔等）
2. Removal of waste products of metabolism (carbon dioxide, urea, creatinine, etc.) 清除代谢废物（二氧化碳、尿素、肌酐等）
3. Hormonal control, by transporting hormones to their target organs and by secreting its own hormones (e.g. atrial natriuretic peptide) 激素控制，通过将激素输送到⽬标器官并分泌其⾃身激素（例如⼼房利钠肽）
4. Temperature regulation, by controlling heat distribution between the body core and the skin (e.g. arteriovenous shunt). 温度调节，通过控制身体核⼼和皮肤
5. Host defense, transporting immune cells, antigen and other mediators (e.g. antibody). 宿主防御，运输免疫细胞、抗原和其他介质（例如抗体）

Circulatory system

1. The Heart (a biological pump)
2. Blood vessels or vascular system (interconnected tubes)
3. Blood (a fluid connective tissue)

Circulatory system consists of the pulmonary circulation and the systemic circulation. As depicted by the color change from blue to red, blood becomes fully oxygenated (red) as it flows through the lungs and then loses some oxygen (red to blue) as it flows through the other organs and tissues.

The systemic circulation: Left ventricle → Aorta → Systemic arteries → Capillaries → Systemic veins → Right atrium

The pulmonary circulation: Right ventricle → Pulmonary arteries → Lungs → Pulmonary capillaries → Pulmonary veins → Left atrium

4.1 The heart

4.1.1 Anatomy [Review]

The heart is a muscular organ enclosed in a protective fibrous sac, the pericardium, and located in the left of chest. A fibrous layer is also closely affixed to the heart and is called the epicardium (心外膜). ⼼脏是⼀个肌⾁器官，位于胸腔左侧，被⼀个保护性的纤维囊（⼼包）包裹着。还有⼀层纤维层紧密贴合在⼼脏上，称为⼼外膜。

Cardiac wall

The wall of the heart, the myocardium, is composed primarily of cardiac muscle cells. The inner surface of the cardiac chambers, as well as the inner wall of all blood vessels, is lined by a thin layer of cells known as endothelial cells, or endothelium. ⼼脏壁，即⼼肌，主要由⼼肌细胞组成。⼼腔内表⾯以及所有⾎管内壁均覆盖⼀层薄薄的细胞，称为内皮细胞或内皮

Valves

Function of valves:

• Prevent backward flow of blood 防⽌⾎液回流
• Open and close in response to pressure gradient across the valve 根据阀⻔上的压⼒梯度打开和关闭

Innervation 支配

Sympathetic nerve → Norepinephrine → β-adrenergic receptor → Entire heart 交感神经 → 去甲肾上腺素 → β‑肾上腺素受体 → 整个⼼脏

Vagus nerve → Acetylcholine → M-muscarinic receptor → Atria 迷⾛神经 → ⼄酰胆碱 → M‑毒蕈碱受体 → ⼼房

Blood Supply

Heart receives their blood supply via arteries that branch from the aorta. The arteries supplying the myocardium are the coronary arteries, and the blood flowing through them is the coronary blood flow. The coronary arteries exit from behind the aortic valve cusps in the very first part of the aorta and lead to a branching network of small arteries, arterioles, capillaries, venules, and veins similar to those in other organs. Most of the cardiac veins drain into a single large vein, the coronary sinus, which empties into the right atrium. ⼼脏通过从主动脉分支出来的动脉获得⾎液供应。供应⼼肌的动脉是冠状动脉，流经冠状动脉的⾎液是冠状动脉⾎流。冠状动脉从主动脉最开始部分的主动脉瓣瓣尖后⾯出来，通向与其他器官类似的⼩动脉、⼩动脉、毛细⾎管、⼩静脉和静脉的分支⽹络。大多数⼼脏静脉流⼊⼀条大静脉，即冠状窦，再流⼊右⼼房。

4.1.2 Mechanical Events of the Cardiac Cycle

心脏的一次收缩和舒张构成的一个机械活动周期，称为心动周期(cardiac cycle)。在一个心动周期中，心房和心室的机械活动都可分为收缩期(systole)和舒张期(diastole)。由于心室在心脏泵血活动中起主要作用，故心动周期通常是指心室的活动周期。Consists of systole (contraction) and then diastole (relaxation) of both atria followed by systole and then diastole of both ventricles.

A typical heart rate is 72 beats/min, and each cardiac cycle lasts approximately 0.8s.

ventricular contraction: 0.3s
ventricular relaxation: 0.5s

atrial contraction: 0.1s
atrial relaxation: 0.7s

Atrial contraction occurs at the end of diastole, after most of the ventricular filling has taken place. The ventricle receives blood throughout most of diastole, not just when the atrium contracts. ⼼房收缩发生在舒张末期，即⼼室充盈大部分时间之后。⼼室在大部分舒张期都会接受⾎液，而不仅仅是在⼼房收缩时

4.1.2.1 Mid-Diastole to Late Diastole

对心室活动周期而言，心房收缩期（period of atrial systole）实际上是前一周期的舒张末期。心房收缩前，心脏处于全心舒张期，此时处于半月瓣关闭、房室瓣开启状态，血液从静脉经心房流入心室，使心室不断充盈。在全心舒张期内，回流入心室的血液量约占心室总充盈量的75%。全心舒张期之后是心房收缩期，历时0.1秒，心房壁较薄、收缩力不强，由心房收缩推动进入心室的血液通常只占心室总充盈量的25%左右。心房收缩时，心房内压和心室内压都轻度升高，但由于大静脉的心房入口处环形肌也收缩，再加上血液向前的惯性，所以虽然大静脉和心房交接处没有瓣膜，心房内的血液很少会反流入大静脉。

1. The left atrium and ventricle are both relaxed, but atrial pressure is slightly higher than ventricular pressure because the atrium is filled with blood that is entering from the veins. 左⼼房和左⼼室均放松，但⼼房压⼒略⾼于⼼室压⼒，因为⼼房充满了从静脉进⼊的⾎液。
2. The AV valve is held open by this pressure difference, and blood entering the atrium from the pulmonary veins continues on into the ventricle. AV 瓣膜在压⼒差的作⽤下保持打开，⾎液从肺静脉继续进⼊⼼室。
3. The aortic valve is closed because the aortic pressure is higher than the ventricular pressure. 由于主动脉压⼒⾼于⼼室压⼒，主动脉瓣关闭。
4. The aortic pressure is slowly decreasing because blood is moving out of the arteries and through the vascular system. 主动脉压⼒缓慢下降，因为⾎液正在流出动脉。
5. In contrast, ventricular pressure is increasing slightly because blood is entering the relaxed ventricle from the atrium. 相反，⼼室压⼒略有增加，因为⾎液进⼊放松的⼼室与⼼房。
6. Near the end of diastole, the SA node discharges and the atria depolarize, as signified by the P wave of the ECG. 舒张末期，窦房结放电，⼼房去极化，表现为⼼电图的 P 波。
7. Atrium contraction of the causes atrial pressure increasing. ⼼房收缩引起⼼房压⼒升⾼。
8. The elevated atrial pressure forces a small additional volume of blood into the ventricle. ⼼房压⼒升⾼迫使少量额外的⾎液进⼊⼼室。
9. The end of ventricular diastole, so the amount of blood in the ventricle at this time is called the end-diastolic volume (EDV). ⼼室舒张末期，此时⼼室内的⾎量称为舒张末期容积（EDV）。

4.1.2.2 Systole 心缩期

• isovolumic contraction period 等容收缩期
• ejection period 射血期
  • period of rapid ejection 快速射血期 70% 0.1s
  • period of reduced ejection 减慢射血期 30% 0.15s

10. From the AV node, the wave of depolarization passes into and throughout the ventricular tissue—as signified by the QRS complex of the ECG—and this triggers ventricular
    contraction. 从房室结开始，去极化波进⼊并穿过⼼室组织（如⼼电图的 QRS 复合波所⽰），从而引发⼼室收缩。

11. As the ventricle contracts, ventricular pressure increases rapidly; almost immediately, this pressure exceeds the atrial pressure. 当⼼室收缩时，⼼室压⼒迅速增加；几乎立即，这压⼒超过⼼房压⼒。

12. This change in pressure gradient forces the AV valve to close, thus preventing the backflow of blood into the atrium. 压⼒梯度的变化迫使 AV 瓣膜关闭，从而防⽌回流⾎液进⼊⼼房。

13. Because the aortic pressure still exceeds the ventricular pressure at this time, the aortic valve remains closed and the ventricle cannot empty despite its contraction. For a brief time, then, all valves are closed during this phase of isovolumetric ventricular contraction. 由于此时主动脉压⼒仍超过⼼室压⼒，主动脉瓣保持关闭状态，⼼室尽管收缩，但⽆法排空。因此，在等容⼼室收缩的这⼀阶段，所有瓣膜都会短暂关闭。

14. This brief phase ends when the rapidly increasing ventricular pressure exceeds aortic pressure. 当快速增加的⼼室压⼒超过主动脉压⼒。

15. The pressure gradient now forces the aortic valve to open, and ventricular ejection begins. 现在压⼒梯度迫使主动脉瓣打开，⼼室射⾎开始。

16. The ventricular volume curve shows that ejection is rapid at first and then slows down. ⼼室容积曲线表现为射⾎起初较快，随后减慢。

17. The amount of blood remaining in the ventricle after ejection is called the end-systolic volume (ESV). 射⾎后⼼室内剩余的⾎液量称为收缩末期⾎流量体积。

    

18. As blood flows into the aorta, the aortic pressure increases along with the ventricular pressure. 当⾎液流⼊主动脉时，主动脉压⼒随着⼼室压⼒的增加而增加。

19. Peak ventricular and aortic pressures are reached before the end of ventricular ejection. 在⼼室射⾎结束之前，⼼室和主动脉压⼒达到峰值。

20. This force reduction is evidenced by the reduced rate of blood ejection during the last part of systole. 这种⼒量的减少可以通过收缩期最后阶段⾎液喷射率的降低来证明。

21. The volume and pressure in the aorta decrease as the rate of blood ejection from the ventricles becomes slower than the rate at which blood drains out of the arteries into the tissues. 由于心室射血速度低于动脉血液流入组织的速度，主动脉的容积和压力会下降。

4.1.2.3 Early Diastole

22. T wave of the ECG corresponds to ventricular repolarization. 心电图的 T 波对应于心室复极化。
23. As the ventricles relax, the ventricular pressure decreases below aortic pressure. The change in the pressure gradient forces the aortic valve to close. 随着心室舒张，心室压力降至主动脉压力以下。压力梯度的变化迫使主动脉瓣关闭。
24. The AV valve also remains closed because the ventricular pressure is still higher than atrial pressure. For a brief time, then, all valves are again closed during this phase of isovolumetric
    ventricular relaxation. AV 瓣膜也保持关闭状态，因为心室压力仍然高于心房压力。然后，在等容心室舒张的这一阶段，所有瓣膜都会短暂地再次关闭。
25. This phase ends as the rapidly decreasing ventricular pressure decreases below atrial pressure. 当快速下降的心室压力降至心房压力以下时，这一阶段结束。
26. This change in pressure gradient results in the opening of the AV valve. 这种压力梯度的变化导致 AV 瓣膜打开。
27. Venous blood that had accumulated in the atrium since the AV valve closed flows rapidly into the ventricles. 自 AV 瓣膜关闭以来，在心房中积聚的静脉血迅速流入心室。
28. The rate of blood flow is enhanced during this initial filling phase by a rapid decrease in ventricular pressure. 在这个初始充盈阶段，心室压力的快速下降提高了血流速度。

• isovolumic relaxation period 等容舒张期

  射血后，心室开始舒张，室内压下降，主动脉内的血液向心室方向反流，推动半月瓣使之关闭；但此时室内压仍高于房内压，故房室瓣仍处于关闭状态，心室又暂时成为一个封闭的腔。从半月瓣关闭至房室瓣开启前的这一段时间内，心室舒张而心室的容积并不改变。

• period of ventricular filling 心室充盈期

  随着心室肌的舒张，室内压进一步下降，当室内压下降到低于房内压时，心房内的血液冲开房室瓣进入心室。

  • period of rapid filling 快速充盈期 2/3 0.11s
  • period of reduced filling 减慢充盈期 0.22s

	AV valves	Semilunar valves
Isovolumetric ventricular contraction 等容⼼室收缩	closed	closed
Ventricular ejection ⼼室射⾎	closed	open
Isovolumetric ventricular relaxation 等容⼼室舒张	closed	closed
Ventricular filling ⼼室充盈	open	closed

4.1.3 The Cardiac Output

Cardiac output (CO): 一侧心室一次心脏搏动所射出的血液量，称为每搏输出量（stroke volume），简称搏出量。一侧心室每分钟射出的血液量，称为心输出量（cardiac output），也称每分输出量或心排出量。The volume of blood each ventricle pumps as a function of time, usually expressed in liters per minute.

正常成年人在安静状态下，左心室舒张期末容积（end-diastolic volume，EDV）约125ml，收缩期末容积（end-systolic volume，ESV）约55ml，两者差值即为搏出量，约70ml（60～80ml）。左、右两侧心室的心输出量基本相等。心输出量等于心率与搏出量的乘积。心输出量与机体的新陈代谢水平相适应，可因性别、年龄及其他生理情况的不同而不同。如果心率为75次/分，搏出量为70ml，则心输出量约为5L/min。一般健康成年男性在安静状态下的心输出量为4.5～6.0L/min。

The cardiac output can be calculated by multiplying the heart rate (HR)—the number of beats per minute—and the stroke volume (SV)—the blood volume ejected by each ventricle with each beat:

$$
CO = HR \times SV
$$

Ejection fraction (EF): 搏出量占心室舒张期末容积的百分比，称为射血分数（ejection fraction）。One way to quantify contractility is through the ejection fraction (EF), defined as the ratio of stroke volume (SV) to enddiastolic volume (EDV):

$$
EF = SV / EDV
$$

一侧心室每分钟射出的血液量，称为心输出量（cardiac output），也称每分输出量或心排出量。左、右两侧心室的心输出量基本相等。心输出量等于心率与搏出量的乘积。
心输出量与机体的新陈代谢水平相适应，可因性别、年龄及其他生理情况的不同而不同。如果心率为75次/分，搏出量为70ml，则心输出量约为5L/min。一般健康成年男性在安静状态下的心输出量为4.5～6.0L/min。

4.1.3.1 Control of heart rate

The slope of phase 4 depolarisation in SA nodal cells determines heart rate.
SA node is normally under the constant influence of nerves and hormones. SA 节点细胞第 4 阶段去极化的斜率决定了心率。SA 节点通常受到神经和激素的持续影响。

Sympathetic neurous: increase
parasympathetic neurous: decrease

In the resting state, more parasympathetic activity to the heart than sympathetic, so the normal resting heart rate of about 70 beats/min is well below the inherent rate of 100 beats/min. 在静息状态下，副交感神经对心脏的活动比交感神经多，因此正常的静息心率约为 70 次/分钟，远低于固有的 100 次/分钟。

Sympathetic stimulation increases the slope of the pacemaker potential by increasing $Na^+$ entering the cell.

Epinephrin 肾上腺素 (Adrenal medulla 肾上腺髓质)
Norepinephrine 去甲肾上腺素
Acetylcholine 甲状腺激素

4.1.3.2 Control of Stroke Volume

1. end-diastolic volume (preload) 前负荷
2. sympathetic regulation 交感神经调节
3. afterload: how hard the heart must work to eject blood 后负荷

• changes in the end-diastolic volume (the volume of blood in the ventricles just before contraction, sometimes referred to as the preload)

  前负荷可使骨骼肌在收缩前处于一定的初长度。对中空、近似球形的心脏来说，心室肌的初长度取决于心室舒张期末的血液充盈量，换言之，心室舒张期末容积相当于心室的前负荷。异长自身调节的生理学意义：异长自身调节的主要生理学意义是对搏出量的微小变化进行精细的调节，使心室射血量与静脉回心血量之间保持平衡，从而使心室舒张期末容积和压力保持在正常范围内。

• changes in the magnitude of sympathetic nervous system input to the ventricles

  • the increased sympathetic nerve stimulation or epinephrine will enhance contraction and stroke volume.
  • 心肌不受副交感神经支配。

  Area Affected	Sympathetic Nerves (Norepinephrine on β-Adrenergic Receptors)	Parasympathetic Nerves (ACh on Muscarinic Receptors)
  SA node	heart rate ↑	heart rate ↓
  AV node	conduction rate ↑	conduction rate ↓
  Atrial muscle	contractility ↑	contractility ↓
  Ventricular muscle	contractility ↑	——

• changes in afterload (i.e., the arterial pressures against which the ventricles pump)

  心室收缩时，必须克服大动脉血压，才能将血液射入动脉内。因此，大动脉血压是心室收缩时所遇到的后负荷。在心肌初长度、收缩能力和心率都不变的情况下，如果大动脉血压增高，等容收缩期室内压的峰值将增高，结果使等容收缩期延长而射血期缩短，射血期心室肌缩短的程度和速度都减小，射血速度减慢，搏出量减少；反之，大动脉血压降低，则有利于心室射血。

4.1.2 Electrophysiology of Cardiac Muscle

根据组织学和电生理学特点，可将心肌细胞分成工作细胞(working cell)和自律细胞(autorhythmic cell)，前者包括心房肌和心室肌，它们有稳定的静息电位，主要执行收缩功能。后者主要包括窦房结细胞和浦肯野细胞，它们组成心内特殊传导系统，大多没有稳定的静息电位，并可自动产生节律性兴奋。

根据心肌细胞动作电位去极化的快慢及其产生机制，又可将心肌细胞分成快反应细胞(fast response cell)和慢反应细胞(slow response cell)。快反应细胞包括心房、心室肌和浦肯野细胞，其动作电位的特点是去极化速度和幅度大，兴奋传导速度快，复极过程缓慢并且可分成几个时相，因而动作电位时程很长。慢反应细胞包括窦房结和房室结细胞，其动作电位特点是去极化速度和幅度小，兴奋传导速度慢，复极过程缓慢而没有明确的时相区分。快反应细胞和慢反应细胞在某些实验条件或病理情况下，可发生转变。

Fast response non-autorhythmic cell: Ventricular and atrial myocardium
Fast response autorhythmic cell: Purkinje cells
Slow response non-autorhythmic cell: Atrioventricular node
Slow response autorhythmic cell: Sinoatrial node

4.1.2.1 Myocardial Cell Action Potentials (Fast response non-autorhythmic cell)

Phase 0: $Na^+$ enters

Phase 1: $K^+$ exits

Phase 2: $K^+$ exits || $Ca^{2+}$​ enters

Phase 3: $K^+$ exits

Phase 4: $Na^+$-$K^+$​ ATPase

4.1.2.2 Nodal Cell Action Potentials (Slow response autorhythmic cell)

Phase 0: $Ca^{2+}$ enters (mainly)

Phase 1: -

Phase 2: -

Phase 3: $K^+$ exits

Phase 4: $Na^+$ enters, $Ca^{2+}$ enters, less $K^+$​ exits over time

This gradual depolarization is known as a pacemaker potential; it brings the membrane potential to threshold, at which point an AP occurs.

4.1.3 Myocardial Characteristics

1. Excitability 兴奋性
2. Autorhythmicity 自律性
3. Conductivity 传导性
4. Contractility 收缩性

Non-autorhythmic cell: 1.3.4.

Autorhythmic cell: 1.2.3.

4.1.3.1 Excitability

心肌细胞每产生一次兴奋，其膜电位将发生一系列规律性变化，兴奋性也因之而产生相应的周期性变化。这种周期性变化，使心肌细胞在不同时期内对重复刺激表现出不同的反应特性，从而对心肌兴奋的产生和传导，甚至对收缩反应产生重要影响。

Excitability: The ability to produce electrical signals that can transmit information between different regions of the membrane. 产生可在膜的不同区域之间传递信息的电信号的能力。

Effective refractory period (ERP) : Absolute refractory period (ARP) + Local response period

• 从0期去极化开始到复极化3期膜电位达-55mV这一段时间内，无论给予多强的刺激，都不会引起心肌细胞产生去极化反应，此段时期称为绝对不应期(absolute refractory period, ARP) 。从复极至-55mV继续复极至-60mV的这段时期内，若给予阈上刺激虽可引起局部反应，但仍不会产生新的动作电位，这一时期称为局部反应期(local response period) 。上述两段时期合称为有效不应期(effective refractory period, ERP) 。此期内心肌细胞兴奋性的暂时缺失或极度下降是由于钠通道完全失活或尚未恢复到可以被激活的备用状态的缘故。但兴奋性的下降是可逆的。心肌的ERP特别长，是兴奋性变化的重要特点。

Relative refactory period (RRP)

• 从膜电位复极化-60mV至-80mV这段时间内，若给予阈上刺激，可使心肌细胞产生动作电位，此期称为相对不应期(relative refractory period , RRP) 。此期已有相当数量的钠通道复活到备用状态，但在阈刺激下激活的钠通道数量仍不足以产生使膜去极化达阈电位的内向电流，故需加强刺激强度方能引起一次新的兴奋。

Supranormal period (SNP)

• 心肌细胞继续复极，膜电位由-80mV 恢复到-90mV 这一段时期，其膜电位值虽低于静息电位，但钠通道已基本恢复到可被激活的备用状态，且膜电位水平与阈电位接近，故一个低于阈值的刺激即可引起一次新的动作电位，此即超常期(supranormal period, SNP) 。

Cardiac muscle is incapable of undergoing summation of contractions like that occurring in skeletal muscle, and this is a very good thing. If a prolonged, tetanic contraction were to occur in the heart, it would cease to function as a pump because the ventricles can adequately fill with blood only while they are relaxed. The inability of the heart to generate tetanic contractions is the result of the long absolute refractory period of cardiac muscle, defined as the period during and following an action potential when an excitable membrane cannot be re-excited. As in the case of neurons and skeletal muscle fibers, the main mechanism is the inactivation of $Na^+$ channels. 该绝对不应期定义为动作电位期间和之后可兴奋膜无法重新兴奋的时期。与神经元和骨骼肌纤维的情况一样，主要机制是 $Na^+$ 通道失活。

The absolute refractory period of skeletal muscle is much shorter (2 to 4 msec) than the duration of contraction (20 to 100 msec), so a second action potential can be elicited while the contraction resulting from the first action potential is still under way (see Figure 9.10). In contrast, because of the prolonged, depolarized plateau in the cardiac muscle action potential, the absolute refractory period of cardiac muscle lasts almost as long as the contraction (approximately 250 msec), and the muscle cannot be re-excited multiple times during an ongoing contraction. 骨骼肌的绝对不应期（2至4毫秒）比收缩持续时间（20至100毫秒）短得多，因此当第一个动作电位引起的收缩仍在进行时，可以引发第二个动作电位。相反，由于心肌动作电位的去极化平台时间较长，心肌的绝对不应期几乎与收缩一样长（约250毫秒），并且在持续的收缩过程中，不能多次重新兴奋。

在正常情况下，当窦房结产生的每一次兴奋传到心房肌和心室肌时，心房肌和心室肌前一次兴奋的不应期均已结束，因此能不断产生新的兴奋，于是，整个心脏就能按照窦房结的节律进行活动。如果在心室肌的有效不应期后，下一次窦房结兴奋到达前，心室受到一次外来刺激，则可提前产生一次兴奋和收缩，分别称为期前兴奋(premature excitation) 和期前收缩(premature systole) 。(形成二联律、三联律) 期前兴奋也有其自身的有效不应期，当紧接在期前兴奋后的一次窦房结兴奋传到心室时，如果正好落在期前兴奋的有效不应期内，则此次正常下传的窦房结兴奋将不能引起心室的兴奋和收缩，即形成一次兴奋和收缩的“ 脱失”‘须待再下一次窦房结的兴奋传来时才能引起兴奋和收缩。这样，在一次期前收缩之后往往会出现一段较长的心室舒张期，称为代偿间歇(compensatory pause)，然后再恢复窦性节律。但窦性心率较慢，下一次窦房结的兴奋也可在期前兴奋的有效不应期结束后才传到心室，在这种情况下，代偿性间歇将不会出现。

4.1.3.2 Autorhythmicity

Autorhythmicity: The capacity for spontaneous, rhythmic self-excitation. ⾃发、有节奏的⾃我兴奋的能⼒。

Sinoatrial node (90-100 beats/min) > Atrioventricular node (40-60 beats/min) > Purkinje fibers (20-40 beats/min)

Pacemaker: Sinoatrial node

Ectopic pacemakers: Atrioventricular node, Purkinje fibers

The pacemaker potential provides the SA node with automaticity, the capacity for spontaneous, rhythmic self-excitation. The slope of the pacemaker potential—that is, how quickly the membrane potential changes per unit time—determines how quickly threshold is reached and the next action potential is elicited. The inherent rate of the SA node—the rate exhibited in the absence of any neural or hormonal input to the node—is approximately 100 depolarizations per minute. Because other cells of the conducting system have slower inherent pacemaker rates, they normally are driven to threshold by action potentials from the SA node and do not manifest their own rhythm.

However, they can do so under certain circumstances and Purkinje network, no longer driven by the SA node, begin to initiate excitation at their own inherent rate and become the pacemaker for the ventricles. Their rate is quite slow, generally 25 to 40 beats/min. Therefore, when the AV node is disrupted, the ventricles contract completely out of synchrony with the atria, which continue at the higher rate of the SA node. Under such conditions, the atria are less effective because they are often contracting when the AV valves are closed. (房室传导阻滞)

起搏器电位为窦房结提供了自律性，即自发、节律性自激的能力。起搏器电位的斜率（即每单位时间膜电位变化的速度）决定了达到阈值和引发下一个动作电位的速度。 SA 节点的固有速率约为每分钟 100 次去极化。 由于传导系统的其他细胞具有较慢的固有起搏器速率，因此它们通常被来自 SA 节点的动作电位驱动到阈值，并且不会表现出它们的心率。自己的节奏。然而，他们可以在某些情况下这样做，并且浦肯野网络不再由 SA 节点驱动，开始以其自身固有的速率启动兴奋，并成为心室的起搏器。它们的速度相当慢，一般为25至40次/分钟。因此，当房室结受到干扰时，心室收缩与心房完全不同步，而心房结以较高的速率继续收缩。在这种情况下，心房的效率较低，因为当房室瓣膜关闭时它们经常收缩。

4.1.3.3 Conductivity

Conductivity: The action potential initiated in the sinoatrial node spreads throughout the myocardium, passing from cell to cell by way of gap junctions ：在⼼房结发起的动作电位传遍整个⼼肌，通过间隙连接从⼀个细胞传递到另⼀个细胞

Purkinje fibers (4m/s) → Bundle of His (2m/s) → Ventricular myocardium (1m/s) → Atrial myocardium (0.4m/s) → Atrioventricular node (0.02m/s)

Atrioventricular node:

• Conducts action potential to ventricles
• Delays action potential to allow atria to complete contraction before ventricles contract 延迟动作电位，使⼼房在⼼室收缩之前完成收缩

Purkinje fibers:

• Large-diameter conduction cells
• Rapidly distribute the impulse throughout much of the ventricles
• Contact with ventricular myocardial cells, and spread the action potential. 与⼼室⼼肌细胞接触，并传播动作电位

4.1.3.4 Contractility

Contractility: Triggered by depolarization of the plasma membrane. 由质膜去极化引发

The heart is a dual pump in that the left and right sides of the heart pump blood separately-but simultaneously-into the systemic and pulmonary vessels. Efficient pumping of blood requires that the atria contract first, followed almost immediately by the ventricles (Synchronous contraction). The initial excitation of one cardiac cell therefore eventually results in the excitation of all cardiac cells (intercalated disc). 有效泵送血液需要心房首先收缩，然后心室几乎立即收缩。与骨骼肌和许多平滑肌一样，心肌的收缩是由质膜的去极化触发的。间隙连接将心肌细胞互连并允许动作电位从一个细胞传播到另一个细胞。一个心肌细胞的初始兴奋最终会导致所有心肌细胞的兴奋。

4.1.4 Electrocardiogram (ECG)

The electrocardiogram (ECG, also abbreviated EKG—the k is from the German elektrokardiogramm) is a tool for evaluating the electrical events within the heart. When action potentials occur simultaneously in many individual (contractile) myocardial cells, currents are conducted through the body fluids around the heart and can be detected by recording electrodes at the surface of the skin. 心电图（ECG，也缩写为 EKG，k 源自德语 elektrokardiogramm）是评估心脏内电活动的工具。当动作电位在许多单独的（收缩性）心肌细胞中同时出现时，电流通过心脏周围的体液传导，并且可以通过皮肤表面的记录电极来检测。

ECG

• Waves
  • P wave
  • QRS wave
  • T wave
• Intervals
  • P-R interval - PR间期代表由窦房结产生的兴奋经由心房、房室交界和房室束到达心室并引起心室肌开始兴奋所需要的时间，故也称为房室传导时间。当发生房室传导阻滞时，PR间期延长。临床上将房室传导功能分为正常、一度阻滞(PR间期延长，无心室漏搏）、二度阻滞(PR可以正常或延长，有心室漏搏）和三度阻滞（心房和心室搏动互不相关，各按自己频率搏动，PP间期<RR间期，P波与QRS波群无关系，PR间期不固定）
  • R-T interval
  • Q-T interval - QT 间期是指从QRS 波起点到T 波终点的时程，代袭芯窒开始去极化到完全复极化所经历的时间。QT 间期的长短与心率成反变关系，心率愈快， QT 间期愈短。QT 间期延长易引起早后去极，并可能诱发严重的室性心律失常——尖端扭转型室性心动过速。
  • P-P interval (R-R interval)
• Segment
  • P-R segment - PR段是指从P波终点到QRS波起点之间的时段，心电图中所描记到的PR段通常出现在基线水平上。PR段反映兴奋通过心房后在向心室传导过程中的电位变化，由于兴奋在通过房室交界区时的传导非常慢，形成的综合电位很小，故在P波之后曲线便回到基线水平，从而形成PR段。
  • S-T segment - ST 段是指从QRS 波群终点到T 波起点之间的线段。由千ST 段代表心室各部分细胞均处千去极化状态（相当于动作电位的平台期），各部分之间的电位差很小。正常时 ST 段应与基线平齐，常描记为一段水平线（等电位线）。心肌缺血或损伤时 ST 段会出现异常压低或抬高。

4.2 The Vascular System

Arteries, Veins and Capillaries

Functions of Endothelial Cells
Serve as a physical lining in heart and blood vessels to which blood cells do not normally adhere 充当心脏和血管中血细胞通常不粘附的物理衬里
Serve as a permeability barrier for the exchange of nutrients, metabolic end products, and fluid between plasma and interstitial fluid; regulate transport of macromolecules and other substances 充当血浆和间质液之间营养物质、代谢终产物和液体交换的渗透性屏障；调节大分子和其他物质的运输
Secrete paracrine agents that act on adjacent vascular smooth muscle cells, including vasodilators such as prostacyclin and nitric oxide (endothelium-derived relaxing factor [EDRF]), and vasoconstrictors such as endothelin-1 分泌作用于邻近血管平滑肌细胞的旁分泌剂，包括前列环素和一氧化氮（内皮源性舒张因子 [EDRF]）等血管舒张剂，以及内皮素-1等血管收缩剂
Mediate angiogenesis (new capillary growth) 介导血管生成（新毛细血管）
Have a central function in vascular remodeling by detecting signals and releasing paracrine agents that act on adjacent cells in the blood vessel wall 通过检测信号并释放作用于血管壁邻近细胞的旁分泌剂，在血管重塑中发挥核心功能
Contribute to the formation and maintenance of extracellular matrix 有助于细胞外基质的形成和维持
Produce growth factors in response to damage 产生生长因子以应对损伤
Secrete substances that regulate platelet clumping, clotting, and anticlotting 分泌调节血小板聚集、凝血的物质和抗凝血
Synthesize active hormones from inactive precursors (Chapter 14) 从非活性前体合成活性激素
Extract or degrade hormones and other mediators (Chapters 11, 13) 提取或降解激素和其他介质
Secrete cytokines during immune responses (Chapter 18) 在免疫反应期间分泌细胞因子
Influence vascular smooth muscle proliferation in the disease atherosclerosis (Chapter 12, Section 12.24) 影响动脉粥样硬化疾病中的血管平滑肌增殖

4.2.1 Functional Classifications of Blood Vessels

Morphological	Physiological Categories	Main Physiological Functions
Large arteries	Windkessel vessels	Buffer the arterial blood pressure and drive the blood flow continuously
Middle arteries	Distribution vessels	Transport the blood into the organs and tissues
Small arteries, arterioles	Precapillary resistance vessels	Maintain the arterial blood pressure and control the blood flow of the organs and tissues
Precapillary sphincters	Precapillary sphincters	Control the opening or closing of the capillaries
Capillaries	Exchange vessels	Are the exchange place between the blood and interstitial fluid
Venules	Postcapillary resistance vessels	Affect the capillary pressure and the filtration
Veins	Capacitance vessels	Contain 60-70% of circulating blood volume
Arteriovenous anastomosis	Shunt vessels	Regulate the body temperature

4.2.2 Arteries

4.2.2.1 Arterial Blood Pressure

Blood pressure (BP): the pressure of circulating blood on the walls of blood vessels. 循环⾎液对⾎管壁的压⼒

Artery blood pressure: the pressure exerted by the blood within the arteries, usually refers to the pressure in the aorta. 动脉内⾎液产生的压⼒，通常指主动脉内的压⼒

Mechanism of BP:

1. Sufficiency of blood in closed loop 闭环⾎液充足
2. Heart contraction ⼼脏收缩
3. Peripheral resistance 外周阻⼒

The pressure inside the artery depends on:

1. the volume of blood ⾎容量
2. how easily the vessel can stretch ⾎管伸展的难易程度

A volume of blood equal to only about one-third of the stroke volume leaves the arteries during systole. The rest of the stroke volume remains in the arteries during systole, distending them and increasing the arterial pressure. When ventricular contraction ends, the stretched arterial walls recoil passively like a deflating balloon, and blood continues to be driven into the arterioles during diastole. 在收缩期离开动脉的血液量仅相当于每搏输出量的三分之一。其余的每搏量在收缩期间保留在动脉中，使动脉扩张并增加动脉压。当心室收缩结束时，拉伸的动脉壁像泄气的气球一样被动地回缩，并且血液在舒张期间继续被推入小动脉。

Systolic arterial pressure (SAP): The maximum arterial pressure reached during peak ventricular ejection 心室射血峰值时达到的最大动脉压

Diastolic arterial pressure (DAP): The minimum arterial pressure occurs just before ventricular ejection begins 最小动脉压发生在心室射血开始之前

Pulse pressure (SAP-DAP): The difference between systolic pressure and diastolic pressure (120 − 80 = 40 mmHg in the example 收缩压和舒张压之间的差值（示例中为 120 − 80 = 40 mmHg）

Mean arterial pressure (MAP): The average pressure during the cycle, referred to as the mean arterial pressure (MAP) 周期内的平均压力，称为平均动脉压（MAP） $MAP=DP+\frac{1}{3}(SP-DP)$

The pressure changes that occur along the rest of the systemic and pulmonary circulations. By the time the blood has completed its journey back to the atrium in each circuit, most of the pressure
originally generated by the ventricular contraction has dissipated. 其余体循环和肺循环中发生的压力变化。当血液在每个回路中完成返回心房的旅程时，最初由心室收缩产生的大部分压力已经消散。

The roles of arterioles 小动脉:

1. The arterioles in individual organs are responsible for determining the relative blood flows to those organs at any given mean arterial pressure. 各个器官中的小动脉负责确定在任何给定的平均动脉压下流向这些器官的相对血流量。
2. The arterioles, all together, are the major factor in determining mean arterial pressure (MAP) itself. 小动脉是决定平均动脉压本身的主要因素。

4.2.2.2 Factors Affecting Arterial Blood Pressure

	SAP	DAP	Pulse pressure	BP
Cardiac output ↑ 心输出量	↑↑	↑	↑	↑
Heart rate ↑ 心率	↑	↑↑	↓	↑
Peripheral resistance ↑ 外周阻⼒	↑	↑↑	↓	↑
Elasticity of aorta and large artery ↓ 主动脉及大动脉弹性	↑	↓	↑↑	↑
Mean circulation filling pressure ↓ 平均循环充盈压⼒	↓↓	↓	↓↓	↓

4.2.2.3 Abnormal Blood Pressure

Abnormally low BP (hypotension): leads to shock, anoxia and tissue destruction.

Chronically elevated BP (hypertension): causes damage because important vessels (especially those of the heart, brain, kidneys and retina) are injured.

4.2.3 Veins

Definition: any of the tubular branching vessels that carry blood from the capillaries toward the heart. 任何一种将血液从毛细血管输送到心脏的管状分支血管。

Function:

1. low-resistance conduits
2. maintaining peripheral venous pressure and venous return to the heart

To aid venous return:

1. Skeletal muscle pump
2. Respiratory pump
3. Venoconstriction - contraction of smooth muscle in wall of vein (sympathetic stimulation) 静脉收缩‑静脉壁平滑肌收缩（交感神经刺激）

Venous smooth muscle contraction, the skeletal muscle pump, and the respiratory pump all work to facilitate venous return and thereby enhance cardiac output by the same amount. 静脉平滑肌收缩、骨骼肌泵和呼吸泵均起作用以促进静脉回流，从而使心输出量增加相同量。

4.2.4 Microcirculation

Distribution: widest

Wall: thinnest

Diameter: smallest

Velocity: slowest

4.2.4.1 Capillaries

Typical capillary is a thin-walled tube of endothelial cells and one layer thick resting on a basement membrane, without any surrounding smooth muscle or elastic tissue. The endothelial cells generally contain large numbers of endocytotic and exocytotic vesicles, and sometimes these fuse to form continuous fused-vesicle channels across the cell. 典型的毛细血管是由内皮细胞组成的薄壁管，厚度为一层，位于基底膜上，周围无任何平滑肌或弹性组织。内皮细胞通常含有大量内吞和外排囊泡，有时这些囊泡融合形成贯穿细胞的连续融合囊泡通道。

4.2.4.2 Arteriolar and Capillary Network

Microcirculation: the blood circulation between the arteriole and venule.

Three pathway of microcirculation

1. Circuity pathway: Nutrient pathway 循环通路：营养通路
2. Thoroughfare channel 通道
3. Arteriovenous shunt: Regulate body temperature 动静脉短路：调节体温

4.2.4.3 Microcirculation Local Controls

Local control of organ blood flow in response to

1. increases in metabolic activity 代谢活动增加
2. decreases in blood pressure ⾎压下降

4.2.5 Formation of Interstitial Fluid

The constituents of interstitial fluid are almost the same as plasma except for much lower concentrations of proteins. Most of interstitial fluid is gelatinous, which cannot flow freely. The substrate of gel consists of collagen fibre bundles and proteoglycan filaments. 组织液的成分与⾎浆基本相同，但蛋白质浓度低得多。组织液大部分呈胶状，不能⾃由流动。胶状基质由胶原纤维束和蛋白聚糖组成。

4.2.5.1 Mechanisms of Interstitial Fluid Formation

Favouring fluid movement out of the capillary: 有利于液体流出毛细⾎管

• $P_c$ (capillary blood hydrostatic pressure); 毛细⾎管⾎液静⽔压
• $π_{IF}$ (osmotic force due to interstitial fluid protein concentration). 由于间质液蛋白质浓度而产生的渗透⼒

Favouring fluid movement into the capillary: 有利于液体进⼊毛细⾎管

• $P_{IF}$ (interstitial hydrostatic pressure); 间质静⽔压⼒
• $π_c$ (osmotic force due to plasma protein concentration); 由于⾎浆蛋白浓度引起的渗透⼒

$$
NFP=P_C+\pi_{IF}-P_{IF}-\pi_C
$$

4.2.6 Lymph Circulation

The lymphatic system is a network of small organs (lymph nodes) and tubes (lymphatic vessels or simply “lymphatics”) through which lymph flows. The lymphatic system is not technically part of the circulatory system, but it is described in this chapter because its vessels provide a route for the movement of interstitial fluid to the circulatory system.

interstitial fluid → lymphatic capillaries → lymph nodes → lymphatic vessels → two large lymphatic ducts → Veins near the junction of the jugular and subclavian veins
间质液 → 毛细淋巴管 → 淋巴结 → 淋巴管 → 两条大淋巴管 → 颈静脉与锁骨下静脉交界处的静脉

Valves at junctions between lymphatic ducts and vascular vessel permit only one-way flow from lymphatic ducts into the veins. Thus, the lymphatic vessels carry interstitial fluid to the cardiovascular system. 淋巴管与⾎管连接处的瓣膜只允许淋巴管单向流⼊静脉。因此，淋巴管将间质液输送到⼼⾎管系统。

Function:

1. Drain excess interstitial fluid to vascular system. 将多余的间质液引流至⾎管系统
2. Drain fat absorbed from the gastrointestinal tract reaches the blood. 排出从胃肠道吸收的脂肪并进⼊⾎液
3. Help cancer cells spread original organ to other parts of the body.

4.3 Regulation of Cardiovascular Activity

4.3.1 Neural Regulation

4.3.1.1 homeostatic control

homeostatic control systems (reflex arc):

An internal environmental variable → Receptors → Afferent pathways → An integrating centre → Efferent pathways → Effectors

To maintain arterial blood pressure at about 120/80 mmHg in the face of changing demands for blood flow to different organs.

MAP= CO × TPR
MAP: Mean systemic arterial pressure
CO: Cardiac output
TPR: Total peripheral resistance

4.3.1.2 Baroreceptor reflexes (depressor reflex, sino-aortic reflex)

The reflexes that homeostatically regulate arterial pressure originate primarily with arterial receptors that respond to changes in pressure. 稳态调节动脉压⼒的反射主要源⾃对压⼒变化作出反应的动脉受体

BP ↑ → sinus nerve (+) / aortic nerve (+) → sympathetic centre (-) / parasympathetic centre (+) / sympathetic vasoconstrictor centre (-) → sympathetic nerve (-) / parasympathetic nerve (+) / sympathetic vasoconstrictor nerve (-)
血压↑ → 窦神经 (+) / 主动脉神经 (+) → 交感神经中枢 (-) / 副交感神经中枢 (+) / 交感血管收缩中枢 (-) → 交感神经 (-) / 副交感神经 (+) / 交感血管收缩神经 (-)

heart: heart rate ↓ / (contraction ↓ → strike volume ↓) → cardiac output ↓ → BP ↓
心脏：心率 ↓ / (收缩 ↓ → 搏动量 ↓) → 心输出量 ↓ → 血压 ↓

vessel: arteriolar constriction ↓ → peripheral resistance ↓ → BP ↓
血管：小动脉收缩 ↓ → 外周阻力 ↓ → 血压 ↓

The baroreceptor reflex functions primarily as a short-term regulator of arterial blood pressure. It is activated instantly by any blood pressure change and functions to restore blood pressure rapidly toward normal. However, if arterial pressure remains increased from its normal set point for more than a few days, the arterial baroreceptors adapt to this new pressure and decrease their frequency of action potential firing at any given pressure. 压力感受器反射主要起短期动脉血压调节器的作用。血压一有变化，压力感受器反射就会立即激活，并起到迅速将血压恢复正常的作用。但是，如果动脉压力持续几天高于正常设定点，动脉压力感受器就会适应这种新压力，并降低在任何给定压力下动作电位发射的频率。

4.3.2 Humoral Regulation

4.3.2.1 Renin-Angiotensin-Aldosterone System (RAAS)

肾素-血管紧张素-醛固酮系统

Aldosterone: 保钠保水排钾 尿量减少

血管紧张素转换酶(ACE)抑制剂：普利类

血管紧张素受体(AT1)阻断剂：沙坦类

4.3.2.2 Epinephrine (E) and Norepinephrine (NE)

	Epinephrine (E)	Norepinephrine (NE)
Resource	Adrenal medulla 肾上腺髓质	Adrenal medulla, sympathetic nerve 肾上腺髓质、交感神经
Function	Cardiotonic 强心剂	Vasopressor 升压药
Heart	β1 receptor: heart rate ↑, myocardial contractility ↑, cardiac output ↑, blood pressure ↑ 心率↑、心肌收缩力↑、心输出量↑、血压↑	β1 receptor: heart rate ↓, myocardial contractility ↑, cardiac output ↑, blood pressure ↑ 心率↓、心肌收缩力↑、心输出量↑、血压↑
Vessel	β2 receptor: vasoconstriction on skin and visceral, while vasodilation on skeletal muscle, heart and liver 皮肤和内脏血管收缩，骨骼肌、心脏和肝脏血管舒张	α1 receptor: vasoconstriction on all organs except for coronary artery, peripheral resistance ↑, DAP ↑ 除冠状动脉外所有器官血管收缩，外周阻力↑，DAP↑
Smooth muscle	Dilation on gastrointestinal tract and bronchus 胃肠道和支气管扩张	Less than Epinephrine
Metabolism	blood glucose ↑, lipolysis ↑, oxygen consumption, heat production ↑ 血糖↑、脂肪分解↑、耗氧量、产热量↑	Less than Epinephrine

4.3.2.3 Blood Volume and Long-term Regulation of AP

The major mechanism for long-term regulation occurs through the blood volume. Blood volume is a major determinant of arterial pressure because it influences venous pressure, venous return, enddiastolic volume, stroke volume, and cardiac output. Thus, increased blood volume increases
arterial pressure. 长期调节的主要机制是通过血容量实现的。血容量是动脉压的主要决定因素，因为它会影响静脉压、静脉回流、舒张末期容积、每搏输出量和心输出量。因此，血容量增加会导致动脉压升高。

An increase in blood pressure for any reason causes a decrease in blood volume, which tends to bring the blood pressure back down. An increase in the blood volume for any reason increases the blood pressure, which tends to bring the blood volume back down. 任何原因引起的血压升高都会导致血容量减少，这往往会使血压回落。任何原因引起的血容量增加都会导致血压升高，这往往会使血容量回落。

Arterial pressure influences blood volume but blood volume also influences arterial pressure, blood pressure can stabilize, in the long run, only at a value at which blood volume is also stable. Consequently, changes in steady-state blood volume are the single most important long-term determinant of blood pressure. 动脉压影响血容量，但血容量也会影响动脉压，从长远来看，血压只能稳定在血容量也稳定的值。因此，稳态血容量的变化是血压最重要的长期决定因素。

利尿剂：氢氯噻嗪

Chapter 11 Reproduction

11.1 Male reproductive physiology

11.2 Female reproductive physiology

11.3 Pregnancy

11.4 Parturition and lactation

Chapter 8 Urine Formation and Excretion

Functions of the kidneys

• Regulation of H2O inorganic ion balance, and acid-base balance (in cooperation with the lungs) (most important function) 水盐平衡
• Removal of metabolic waste products from the blood and their excretion in the urine
• Removal of foreign chemicals from the blood and their excretion in the urine
• Gluconeogenesis 糖异生
• Production of hormones / enzymes:
  • Erythropoietin, which controls erythrocyte production 促红细胞生成素，控制红细胞的产生
  • Renin, an enzyme that controls the formation of angiotensin, which influences blood pressure and sodium balance 肾素，一种控制血管紧张素形成的酶，血管紧张素影响血压和钠平衡
  • Conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, which influences calcium balance 25-羟基维生素 D 转化为 1,25-二羟基维生素 D，影响钙平衡

肾脏是机体最重要的排泄器官，通过尿的生成和排出，肾脏能够排出机体代谢终产物、进入机体过剩的物质和异物，调节水、电解质和酸碱平衡，调节动脉血压等，从而维持机体内环境的稳态。肾脏也是一个内分泌器官，它能合成和释放多种生物活性物质，如合成和释放肾素，参与动脉血压的调节；合成和释放促红细胞生成素，促进红细胞的生成；肾脏中的1α-羟化酶可使25-羟维生素D3转化为1,25-二羟维生素D3， 调节钙的吸收和血钙水平；肾脏还能生成激肽和前列腺素，参与局部或全身血管活动的调节。

8.1 Structure of the Kidneys and Urinary System

8.1.1 Renal Nephron

• Kidneys have an excellent blood supply: 0.5% total body weight but ~20% of CO (Cardiac Output).
• Kidneys process plasma portion of blood by removing substances from it, and in a few cases, by adding substances to it.
• Works with cardiovascular system and others in integrated manner.

The two kidneys lie at the back of the abdominal wall but not actually in the abdominal cavity. They are retroperitoneal, meaning they are just behind the peritoneum, the lining of this cavity. The urine flows from the kidneys through the ureters into the bladder and then is eliminated via the urethra (Figure 14.1). The major structural components of the kidney are shown in cross section in Figure 14.2. The indented surface of the kidney is called the hilum, through which courses the blood vessels perfusing (renal artery) and draining (renal vein) the kidneys. The nerves that innervate the kidney and the tube that drains urine from the kidney (the ureter) also pass through the hilum. The ureter is formed from the calyces (singular, calyx), which are funnel-shaped structures that drain urine into the renal pelvis, from which the urine enters the ureter. Also notice that the kidney is surrounded by a protective capsule made of connective tissue. The kidney is divided into an outer renal cortex and inner renal medulla, described in more detail later. The connection between the tip of the medulla and the calyx is called the papilla.

两个肾脏位于腹壁后部，但实际上并不在腹腔内。它们是腹膜后的，这意味着它们位于腹膜（该腔的内壁）后面。尿液从肾脏通过输尿管流入膀胱，然后通过尿道排出（图14.1）。肾脏的主要结构部件如图 14.2 中的横截面所示。肾脏的凹进表面称为肾门，灌注肾脏（肾动脉）和引流肾脏（肾静脉）的血管穿过该肾门。支配肾脏的神经和从肾脏排出尿液的管道（输尿管）也穿过肺门。输尿管由肾盏（单数，calyx）形成，肾盏是漏斗状结构，将尿液排入肾盂，尿液从肾盂进入输尿管。另请注意，肾脏被结缔组织制成的保护性胶囊包围。肾脏分为外肾皮质和内肾髓质，稍后将更详细地描述。髓质尖端和花萼之间的连接称为乳头。

• Total of about 2.5 million in the 2 kidneys.

• Each nephron consists of 2 functional components:

  • an initial filtering component called the renal corpuscle
  • a tubule that extends from the renal corpuscle

  …..

Each nephron consists of:

1. an initial filtering component called the renal corpuscle: glomerulus, Bowman’s capsule
2. a tubule that extends from the renal corpuscle

Each renal corpuscle contains a compact tuft of interconnected capillary loops called the glomerulus or glomerular capillaries.

Each glomerulus is supplied with blood by an arteriole called an afferent arteriole.

The glomerulus protrudes into a fluid-filled capsule called Bowman’s capsule.

The combination of a glomerulus and a Bowman’s capsule constitutes a renal corpuscle. As blood flows through the glomerulus, about 20% of the plasma filters into Bowman’s capsule. The remaining blood then leaves the glomerulus by the efferent arteriole.

The part of Bowman’s capsule in contact with the glomerulus becomes pushed inward but does not make contact with the opposite side of the capsule. Accordingly, a fluid-filled space called the Bowman’s space exists within the capsule. Fluid essentially free of proteins filters from the glomerulus into this space.

• two sets of capillaries in the kidneys:
  • the glomerular capillaries
  • the peritubular capillaries
• two sets of arterioles capillaries int he kidneys:
  • the afferent arteriole
  • the efferent arteriole
• the renal circulation is very unusual in that it includes two sets of arterioles…

Two types of nephrons are shown—the juxtamedullary nephrons have long loops of Henle that penetrate deeply into the medulla, whereas the cortical nephrons have short (or no) loops of Henle. 近髓肾单位具有深入髓质的长亨利环，而皮质肾单位具有短（或无）亨利环。

致密斑不是一个独特的部分，而是亨利升袢中的细胞斑块，该袢在供应其起源肾小体的小动脉之间穿过。皮质是所有肾小体所在的地方。在髓质中，亨利环和集合管彼此平行。髓质集合管流入肾盂。显示了两种类型的肾单位——近髓肾单位具有深入髓质的长亨利环，而皮质肾单位具有短（或无）亨利环。请注意，近髓肾单位的传出小动脉产生称为直血管的长的环状毛细血管，而皮质肾单位的传出小动脉产生管周毛细血管。未显示（为了清楚起见）围绕位于皮质中的近髓肾单位小管部分的管周毛细血管。这些管周毛细血管主要来自其他皮质肾单位。

8.1.2 Juxtaglomerular Apparatus

Glomerular filtrate drains into Bowman’s space, and then into proximal convoluted tubule.

Endothelium has pores to allow small molecules through.

Podocytes have negative charge. This and the basement membrane stops proteins getting through into tubular fluid.

Macula densa senses GFR by [Na^+^]

Juxtaglomerular (JG) apparatus also includes JG cells that secrete renin.

JGA helps regulate renal blood flow, GFR and also indirectly, modulates Na^+^ balance and systemic BP.

One additional anatomical detail involving both the tubule and the arterioles is important. Near its end, the ascending limb of each loop of Henle passes between the afferent and efferent arterioles of that loop’s own nephron (see Figure 14.3). At this point, there is a patch of cells in the wall of the ascending limb as it becomes the distal convoluted tubule called the macula densa, and the wall of the afferent arteriole contains secretory cells known as juxtaglomerular (JG) cells. The combination of macula densa and juxtaglomerular cells is known as the juxtaglomerular apparatus (JGA) (see Figure 14.4a and Figure 14.5). As described later, the JGA has important functions in the regulation of ion and water balance, and the production of factors that control blood pressure. 涉及小管和小动脉的另一项解剖细节很重要。在其末端附近，每个亨利环的升肢在该环自身肾单位的传入和传出小动脉之间穿过（见图 14.3）。此时，升肢的壁上有一片细胞，因为它成为远端曲管，称为致密斑，传入小动脉的壁包含称为肾小球旁（JG）细胞的分泌细胞。致密斑和肾小球旁细胞的组合被称为肾小球旁装置（JGA）（见图 14.4a 和图 14.5）。如下所述，JGA在离子和水平衡的调节以及控制血压的因子的产生方面具有重要的功能。

8.2 Basic Renal Processes

The three basic renal processes:

• Glomerular filtration
• Tubular reabsorption
• Tubular secretion

$$ Amount\ excreted = Amount\ filtered + Amount\ secreted - Amount\ reabsorbed $$

8.2.1 Glomerular Filtration

The volume of fluid filtered from the glomeruli into Bowman’s space per unit time is known as the glomerular filtration rate (GFR). GFR is determined by:

1. the net filtration pressure
2. the permeability of the corpuscular membranes
3. the surface area available for filtration

At any given net filtration pressure, the GFR will be directly proportional to the membrane permeability and the surface area.

• GFR controlled by diameters of afferent and efferent arterioles
• Sympathetic vasoconstrictor nerves
• ADH and RAAS also have an effect on GFR
• Autoregulation maintains blood supply and so maintains GFR. Also prevents high pressure surges damaging kidneys.
• Remember: high hydrostatic pressure (PGC) at glomerular capillaries is due to short, wide afferent arteriole (low R to flow) and the long, narrow efferent arteriole (high R).

GFR depends on diameters of afferent and efferent arterioles

Control of GFR by constriction or dilation of afferent arterioles (AA) or efferent arterioles (EA). (a) Constriction of the afferent arteriole or (c) dilation of the efferent arteriole reduces PGC, thus decreasing GFR. (b) Constriction of the efferent arteriole or (d) dilation of the afferent arteriole increases PGC, thus increasing GFR. 通过收缩或扩张传入小动脉 (AA) 或传出小动脉 (EA) 来控制 GFR。 (a) 传入小动脉收缩或 (c) 传出小动脉扩张会降低 PGC，从而降低 GFR。 (b) 传出小动脉收缩或 (d) 传入小动脉扩张会增加 PGC，从而增加 GFR。

8.2.2 Tubular Reabsorption

GFR (glomerular filtration rate) is very high: ~180L/day. Lots of opportunity to precisely regulate ECF (extracellular fluid) and get rid of unwanted substances.

It is the ECF that is being regular ……

Assume that the tubule can secrete 100% of the peritubular capillary substance X into the tubular lumen but cannot reabsorb X. Therefore, by the combination of filtration and tubular secretion, the plasma that originally entered the renal artery is cleared of all of its substance X, which leaves the body via the urine. Logically, this tends to be the pattern for renal handling of foreign substances that are potentially harmful to the body. By contrast, assume that the tubule can reabsorb but not secrete Y and Z. The amount of Y reabsorption is moderate so that some of the filtered material is not reabsorbed and escapes from the body. For Z, however, the reabsorptive mechanism is so powerful that all the filtered Z is reabsorbed back into the plasma. Therefore, no Z is lost from the body. Hence, for Z, the processes of filtration and reabsorption have canceled each other out and the net result is as though Z had never entered the kidney. Again, it is logical to assume that substance Y is important to retain but requires maintenance within a homeostatic range; substance Z is presumably very important for health and is therefore completely reabsorbed. 假设肾小管可以将100%的肾小管周围毛细血管物质X分泌到肾小管腔内，但不能重吸收X。因此，通过滤过和肾小管分泌的结合，最初进入肾动脉的血浆中的所有物质X被清除，通过尿液离开身体。从逻辑上讲，这往往是肾脏处理对身体可能有害的异物的模式。相比之下，假设肾小管可以重吸收但不分泌Y和Z。Y重吸收的量是适中的，因此一些过滤的物质不会被重吸收并从体内逸出。然而，对于 Z 而言，重吸收机制非常强大，以至于所有过滤的 Z 都会被重吸收回血浆中。因此，Z 不会从体内丢失。因此，对于 Z 来说，过滤和重吸收过程相互抵消，最终结果就好像 Z 从未进入肾脏一样。同样，假设物质 Y 很重要，但需要维持在稳态范围内，这是合乎逻辑的； Z 物质可能对健康非常重要，因此会被完全重新吸收。

• The filtered loads are enormous, generally larger than the total amounts of the substances in the body. For example, the body contains about 40 L of water, but the volume of water filtered each day is 180 L.
• Reabsorption of waste products is relatively incomplete (as in the case of urea), so that large fractions of their filtered loads are excreted in the urine.
• Reabsorption of most useful plasma components, such as water, inorganic ions, and organic nutrients, is relatively complete so that the amounts excreted in the urine are very small fractions of their filtered loads.

8.2.2.1 Control of reabsorption rate

The reabsorption rates of most organic nutrients, such as glucose, are always very high and are not physiologically regulated. Therefore, the filtered loads of these substances are completely reabsorbed in a healthy kidney, with none appearing in the urine. For these substances, like substance Z in Figure 14.7, it is as though the kidneys do not exist because healthy kidneys do not eliminate these substances from the body at all. Therefore, the kidneys do not regulate the plasma concentrations of these organic nutrients. Rather, the kidneys merely maintain whatever plasma concentrations already exist. 大多数有机营养素（例如葡萄糖）的重吸收率总是非常高并且不受生理调节。因此，这些物质的过滤负荷完全被健康肾脏重新吸收，尿液中不会出现任何物质。对于这些物质，如图 14.7 中的 Z 物质，就好像肾脏不存在一样，因为健康的肾脏根本不会将这些物质从体内消除。因此，肾脏不调节这些有机营养素的血浆浓度。相反，肾脏只是维持已经存在的血浆浓度。

The reabsorptive rates for water and many ions, although also very high, are under physiological control. For example, if water intake is decreased, the kidneys can increase water reabsorption to minimize water loss. 水和许多离子的重吸收率虽然也很高，但受到生理控制。例如，如果水摄入量减少，肾脏可以增加水的重吸收，以最大限度地减少水的流失。

In contrast to glomerular filtration, the crucial steps in tubular reabsorption do not occur by bulk flow because there are inadequate pressure differences across the tubule and limited permeability of the tubular membranes. Instead, two other processes are involved: 肾小管上的压差不足并且肾小管膜的渗透性有限

• The reabsorption of some substances from the tubular lumen is by diffusion, often across the tight junctions connecting the tubular epithelial cells (Figure 14.10). 一些物质从肾小管腔的重吸收是通过扩散进行的，通常穿过连接肾小管上皮细胞的紧密连接。
• The reabsorption of all other substances involves mediated transport, which requires the participation of transport proteins in the plasma membranes of tubular cells. 所有其他物质的重吸收都涉及介导的转运，这需要肾小管细胞质膜中转运蛋白的参与。

8.2.2.2 Reabsorption by Diffusion

The reabsorption of urea by the proximal tubule provides an example of passive reabsorption by diffusion.

• Some urea is reabsorbed from the proximal tubule in a process that facilitates water reabsorption farther down the nephron.
• Because the corpuscular membranes are freely filterable to urea, the urea concentration in the fluid within Bowman’s space is the same as that in the peritubular capillary plasma and the interstitial fluid surrounding the tubule.
• Then, as the filtered fluid flows through the proximal tubule, water reabsorption occurs (by mechanisms to be described later). This removal of water increases the concentration of urea in the tubular fluid so it is higher than in the interstitial fluid and peritubular capillaries.
• Therefore, urea diffuses down this concentration gradient from tubular lumen to peritubular capillary.
• Urea reabsorption is thus dependent upon the reabsorption of water. 近曲小管对尿素的重吸收提供了通过扩散被动重吸收的例子。对近曲小管中尿素浓度的分析将有助于阐明其机制。如上所述，尿素是一种废物；然而，正如您很快就会了解到的那样，一些尿素会从近端肾小管重新吸收，这一过程有利于肾单位更深处的水重新吸收。由于红细胞膜可自由过滤尿素，鲍曼间隙内液体中的尿素浓度与肾小管周围毛细血管血浆和肾小管周围间质液中的尿素浓度相同。然后，当过滤后的液体流过近端小管时，会发生水的重吸收（通过稍后描述的机制）。这种水的去除增加了肾小管液中尿素的浓度，因此其浓度高于间质液和肾小管周围毛细血管中的尿素浓度。因此，尿素沿着该浓度梯度从肾小管腔扩散到肾小管周围毛细血管。因此，尿素重吸收取决于水的重吸收。

8.2.2.3 Reabsorption by Mediated Transport

Many solutes are reabsorbed by primary or secondary active transport. These substances must first cross the apical membrane (also called the luminal membrane) that separates the tubular lumen from the cell interior. Then, the substance diffuses through the cytosol of the cell and, finally, crosses the basolateral membrane, which begins at the tight junctions and constitutes the plasma membrane of the sides and base of the cell. The movement by this route is termed transcellular epithelial transport.

A substance does not need to be actively transported across both the apical and basolateral membranes in order to be actively transported across the overall epithelium, moving from lumen to interstitial fluid against its electrochemical gradient.

For example, Na+ moves “downhill” (passively) into the cell across the apical membrane through specific channels or transporters and then is actively transported “uphill” out of the cell across the basolateral membrane via Na+/K+-ATPases in this membrane.

The reabsorption of many substances is coupled to the reabsorption of Na+. The cotransported substance moves uphill into the cell via a secondary active cotransporter as Na+ moves downhill into the cell via this same cotransporter. This is precisely how glucose, many amino acids, and other organic substances undergo tubular reabsorption. The reabsorption of several inorganic ions is also coupled in a variety of ways to the reabsorption of Na+. 许多溶质通过初级或次级主动转运被重吸收。这些物质必须首先穿过将管状腔与细胞内部分开的顶膜（也称为腔膜）。然后，物质扩散通过细胞的细胞质，最后穿过基底外侧膜，基底外侧膜从紧密连接处开始，构成细胞侧面和基底的质膜。通过该途径的运动称为跨细胞上皮运输。物质不需要主动转运穿过顶膜和基底外侧膜，以便主动转运穿过整个上皮，逆其电化学梯度从管腔移动到间质液。例如，Na+通过特定通道或转运蛋白穿过顶膜“下坡”（被动）进入细胞，然后通过基底外侧膜通过该膜中的Na+/K+-ATP酶主动“上坡”运输出细胞。许多物质的重吸收与Na+的重吸收相关。当 Na+ 通过相同的协同转运蛋白下坡进入细胞时，协同转运物质通过次级活性协同转运蛋白上坡进入细胞。这正是葡萄糖、许多氨基酸和其他有机物质经历肾小管重吸收的方式。几种无机离子的重吸收也以多种方式与Na+的重吸收耦合。

Many of the mediated-transport-reabsorptive systems in the renal tubule have a limit to the amounts of material they can transport per unit time known as the transport maximum ($T_m$). This is because the binding sites on the membrane transport proteins become saturated when the concentration of the transported substance increases to a certain level. 肾小管中的许多介导转运重吸收系统对单位时间内可转运的物质量有限制，称为最大转运量。这是因为当转运物质的浓度增加到一定水平时，膜转运蛋白上的结合位点变得饱和。

Secondary active-transport proteins for glucose, located in the proximal tubule.

Glucosuria

When the filtered load of glucose exceeds the glucose transport maximum for a significant number of nephrons (typically during hyperglycaemia), glucose starts to appear in urine. *in people with sustained hyperglycaemia (for example, in poorly controlled diabetes mellitus), 当葡萄糖的过滤负荷超过大量肾单位的葡萄糖转运最大值时（通常在高血糖期间），葡萄糖开始出现在尿液中。持续高血糖的人（例如，糖尿病控制不佳）

8.2.2.4 “Division of Labour” in the Tubules

The primary role of the proximal tubule is to reabsorb most of this filtered water and these solutes. 近端小管的主要作用是重新吸收大部分过滤水和这些溶质。此外，除了 K+ 以外，近曲小管是溶质分泌的主要部位。

Furthermore, with K+ as a major exception, the proximal tubule is the major site of solute secretion. Henle’s loop also reabsorbs relatively large quantities of the major ions and, to a lesser extent, water. 亨利环还重新吸收相对大量的主要离子，并在较小程度上重新吸收水。

Extensive reabsorption by the proximal tubule and Henle’s loop ensures that the masses of solutes and the volume of water entering the tubular segments beyond Henle’s loop are relatively small. 近端小管和亨利袢的广泛重吸收确保了进入亨利袢之外的管状段的溶质质量和水量相对较小。

These distal segments then do the fine-tuning for most low-molecular-weight substances, determining the final amounts excreted in the urine by adjusting their rates of reabsorption and, in a few cases, secretion. 然后，这些远端部分对大多数低分子量物质进行微调，通过调整其重吸收率以及在少数情况下的分泌率来确定尿液中排泄的最终量。

Most homeostatic controls act upon the more distal segments of the tubule. 大多数稳态控制作用于肾小管的更远端部分。

8.3 Renal Clearance

A useful way of quantifying renal function is in terms of clearance. The renal clearance of any substance is the volume of plasma from which that substance is completely removed (“cleared”) by the kidneys per unit time. Every substance has its own distinct clearance value, but the units are always in volume of plasma per unit of time. The basic clearance formula for any substance S is
$$
Clearance\ of\ S = \frac{Mass\ of\ S\ excreted\ per\ unit\ time}{plasma\ concentration\ of\ S}
$$

The renal clearance of any substance is the volume of plasma from which that….

……

8.4 Total-Body Balance of Sodium and Water

8.5 Basic Renal Processes for Sodium and Water

8.5.1 Primary Active Na+ Reabsorption

The bulk of Na and water reabsorption (about two-thirds) occurs in the proximal tubule, but the major hormonal control of reabsorption is exerted on the distal convoluted tubules and collecting ducts.

The mechanisms of Na+ and water reabsorption can be summarized in two generalizations:

• Na+ reabsorption is an active process occurring in all tubular segments except the descending limb of the loop of Henle.
• Water reabsorption is by osmosis (passive) and is dependent upon Na+ reabsorption.

8.5.2 Coupling of Water Reabsorption to Na+ Reabsorption

1. Na+ is transported from the tubular lumen to the interstitial fluid across the epithelial cells. Other solutes, such as glucose, amino acids, and HCO3−, whose reabsorption depends on Na+ transport, also contribute to osmosis. Na+ 从肾小管腔穿过上皮细胞转运至间质液。其他溶质，如葡萄糖、氨基酸和 HCO3−，其重吸收依赖于 Na+ 转运，也有助于渗透。
2. The removal of solutes from the tubular lumen decreases the local osmolarity of the tubular fluid adjacent to the cell (i.e., the local water concentration increases). At the same time, the appearance of solute in the interstitial fluid just outside the cell increases the local osmolarity (i.e., the local water concentration decreases). 从管状腔中去除溶质会降低细胞附近管状液体的局部渗透压（即局部水浓度增加）。同时，细胞外间质液中溶质的出现增加了局部渗透压（即局部水浓度降低）。
3. The difference in water concentration between lumen and interstitial fluid causes net diffusion of water from the lumen across the tubular cells’ plasma membranes and/or tight junctions into the interstitial fluid. 管腔和间质液之间的水浓度差异导致水从管腔穿过肾小管细胞的质膜和/或紧密连接进入间质液的净扩散。
4. From there, water, Na+, and everything else dissolved in the interstitial fluid move together by bulk flow into peritubular capillaries as the final step in reabsorption. 从那里，水、Na+ 和溶解在间质液中的其他物质一起大量流入肾小管周围毛细血管，作为重吸收的最后一步。

8.5.3 AQPs

Water permeability varies from tubular segment to segment and depends largely on the presence of water channels, called aquaporins, in the plasma membranes.

The proximal tubule reabsorbs large amounts of Na and water in the same proportions.

Crucial point: the water permeability of the cortical and medullary collecting ducts, can vary greatly due to physiological control. These are the only tubular segments in which water permeability is under such control.

ADH

The major determinant of this controlled permeability and, therefore, of passive water reabsorption in the collecting ducts is a peptide hormone secreted from the posterior pituitary and known as vasopressin, or antidiuretic hormone (ADH; see Chapter 11). Vasopressin stimulates the insertion into the apical membrane of a particular aquaporin water channel made by the collecting-duct cells. More than 10 different aquaporins have been identified throughout the body, and they are identified as AQP1, AQP2, and so on. Figure 14.16 shows the function of the aquaporin water channels in the cells of the collecting ducts. 这种受控渗透性以及集合管中被动水重吸收的主要决定因素是垂体后叶分泌的肽激素，称为加压素或抗利尿激素（ADH；参见第 11 章）。加压素刺激由集合管细胞形成的特定水通道蛋白水通道插入顶膜。全身各处已鉴定出10多种不同的水通道蛋白，它们被鉴定为AQP1、AQP2等。图 14.16 显示了集合管细胞中水通道蛋白水通道的功能。

diuresis: large urine flow

• water diuresis (low ADH)
• osmotic diuresis (increase in solute secretion)

diabetes insipidus: ADH disorder

• central diabetes insipidus (failure of ADH release)
• nephrogenic diabetes insipidus (inability of kidney to respond to ADH)

any loss of ……

8.5.4 Urine Concentration: The Countercurrent Multiplier System 逆流倍增系统

• hypoosmotic, isoosmotic, hyperosmotic
• obligatory water loss 这个尿液量被称为每日强制性失水量。当饮水量非常低时，这种最小量尿液的流失会导致脱水。

Urinary concentration takes place as tubular fluid flows through the medullary collecting ducts. The interstitial fluid surrounding these ducts is very hyperosmotic. In the presence of vasopressin, water diffuses out of the ducts into the interstitial fluid of the medulla and then enters the blood vessels of the medulla to be carried away.

当管状液体流经髓质集合管时，尿液就会浓缩。这些导管周围的间质液渗透压非常高。在加压素存在的情况下，水从导管扩散到髓质的间质液中，然后进入髓质的血管被带走。

……

Chapter 10 Endocrine Physiology

10.1 General characteristics of hormones

10.2 Endocrine of the hypothalamus and pituitary gland

10.3 Endocrine of the thyroid gland

10.4 Endocrine of the adrenal gland

10.5 Endocrine of the pancreatic islet

10.6 Endocrine control of the homeostasis of calcium and phosphate

10.7 Other endocrine glands and hormones

Chapter 9 Functions of the Nervous System

9.1 General principles of activities of the nervous system

9.2 Sensory functions of the nervous system

9.3 Control of body movement

9.4 Autonomic nervous system

9.5 Electrical activity of the brain, wakefulness and sleep

9.6 High functions of the brain

Chapter 7 Energy metabolism and body Temperature

7.1 Energy metabolism

7.2 Body temperatures and its control