Week 1 and 2 Review

Homeostasis

Process of maintaining the “constancy” of our internal environment

What % of body weight in an adult does total body water account for?

~60%

What are the 3 compartments that total body water is divided into?

Intracellular

Interstitial

Plasma

What fraction of total body water does intracellular fluid make up?

2/3

Interstitial Fluid

• • Immediate environment of individual cells

    • Cells draw their nutrients from and release their products into the interstitial fluid

  • Cannot be a large reservoir for nutrients or a large sink for metabolic products because its volume is less than half that of the cells that it serves

  • Well-being of individual cells depends heavily on the homeostatic mechanisms that regulate the composition of the interstitial fluid

    • Accomplished by continuously exposing the interstitial fluid to "fresh" circulating plasma fluid

      • As blood passes through capillaries, solutes exchange between plasma and interstitial fluid by diffusion

      • Result is that interstitial fluid tends to take on the composition of incoming blood

What % of blood volume do suspended blood cells occupy?

~40%

What are the 3 conditions provided by the cardiovascular system that are essential for regulating the composition of the interstitial fluid?

• There must be adequate blood flow through the tissue capillaries

• The chemical composition of the incoming (or arterial) blood must be controlled to be that which is optimal in the interstitial fluid

• Diffusion distances between plasma and tissue cells must be short

  • No cell in the body is located farther than ~10 um from a capillary

  • Diffusion is a poor mechanism for moving substances from the capillaries of an organ to the capillaries of another organ than may be 1 m or more distant

    • Substances are transported between organs by convection - substances move along with blood flow because there are either dissolved or contained within blood

What condition must be present for fluid to flow through a tube?

Fluid flows through the tube only when the pressure at the inlet and outlet ends (P_i  and P_o) are unequal, when there is a pressure difference (ΔP )

Vascular Resistance

Measure of how difficult it is to make fluid flow through the tube (how much of a pressure difference it takes to cause a certain flow

Flow Equation

What are the 2 ways in which blood flow through any organ can be changed?

By changing the pressure difference across its vascular bed

By changing its vascular resistance

• More often changes in flow due to changes in vascular resistance

Resistance to Flow Through a Cylindrical Tube

Resistance to flow through a cylindrical tube depends on radius and length of the tube and the viscosity of the fluid flowing through it

• Small changes in internal radius have a huge influence on resistance to flow

Resistance to Flow Through a Cylindrical Tube Equation

Poiseuille Equation

Regulation of Blood Flow Through Organs

• Organ blood flows are regulated primarily through changes in the radii of vessels within organs

• Vessel length and blood viscosity are not variable that can be easily manipulated for the purpose of moment-to-moment control of blood flow

• Blood flows through vessels within an organ because a pressure difference exists between the blood in the arteries supplying the organ and the veins draining it

  • Normally average pressure in systemic arteries is approximately 100 mm Hg, and the average pressure in systemic veins is approximately 0 mm Hg

Convective Transport

Process of being swept along with the flow of the blood in which substances are contained

• Rate at which the substance is transported by this process depends solely on the concentration of the substance in the blood and the blood flow rate

Transport Rate Equation

What are the two methods available for altering the rate at which a substance is carried to an organ?

A change in the blood flow rate through the organ

A change in the arterial blood concentration of the substance

What do you need to consider to calculate the rate at which a substance is being removed from (or added to) the blood as it passes through an organ?

To calculate the rate at which a substance is being removed from (or added to) the blood as it passes through an organ you have to simultaneously consider the rate at which the substance is entering the organ in the arterial blood and the rate at which the substance is leaving the organ in the venous blood

Transcapillary Efflux Rate Equation

• Used to deduce a tissue's steady-state rate of consumption (or production) of any substance

• When a substance enters a tissue from the blood it can either increase the concentration of itself within the tissue or be metabolized within the tissue

• In the steady state, the rate of the substance's loss from blood within a tissue must equal its rate of metabolism within that tissue

Chambers and Valves of the Heart and Pathway of Blood Flow Through Them

• Venous blood returns from the systemic organs to the right atrium via the superior and inferior venae cavae

  • Passes through the tricuspid valve into the right ventricle and then is pumped through the pulmonic valve into the pulmonary circulation via the pulmonary arteries

• Blood is reoxygenated in the capillaries of the lung

• Oxygenated pulmonary venous blood flows in pulmonary veins to the left atrium and passes through the mitral valve into the left ventricle

  • Pumped through the aortic valve into the aorta to be distributed to the systemic organs

Pressure Changes Across the Heart Valves and in the Chambers that Lead to Blood Flow

• Valves are structurally designed to allow flow in only one direction and passively open and close in response to the direction of the pressure differences across them

• Ventricular pumping action occurs because the volume of the intraventricular chamber is cyclically changed by rhythmic and synchronized contraction and relaxation of the individual cardiac muscle cells that lie in a circumferential orientation within the ventricular wall

• As soon as ventricular pressure exceeds the pressure in the pulmonary artery (right pump) or aorta (left pump) blood is forced out of the chamber through the outlet valve

Systole

Phase of the cardiac cycle during which the ventricular muscles contract

• Contraction of the ventricular muscle increases tension in the chordae tendinae which prevents the AV valve from opening despite the large pressure difference between the ventricle and atrium

Diastole

When the ventricular muscle cells relax, the pressure in the ventricle falls below that in the atrium, the AV valve opens, and the ventricle refills with blood

• The outlet valve is closed during diastole because arterial pressure is greater than intraventricular pressure

Cardiac Output Equation

• CO determined by stroke volume and heart rate

  • Stroke volume - volume of blood ejected per beat

  • Heart rate - heart beats per minute

• CO = SV x HR

Stroke Volume Equation

• Stroke volume must equal the blood volume inside the ventricle at the end of diastole (end diastolic volume, EDV), minus ventricular volume at the end of systole (end systolic volume, ESV)

  • SV = EDV - ESV

How are action potentials conducted from one cell to the next?

Via gap junctions

Components of the Cardiac Excitation and Conduction System

• Components of excitation and conduction system

  • Sinoatrial node (SA node)

    • Contains cells that function as the heart's pacemaker and initiate the action potential

  • Atrioventricular node (AV node)

    • Contains slowly conducting cells that normally function to create a slight delay between atrial contraction and ventricular contraction

  • Bundle of His

  • Right and left bundle branches

    • Made up of Purkinje fibers

      • Specialized for rapid conduction and ensure that all ventricular cells contract at the same instant

What normally controls the heart rate?

Electrical activity of SA nodal cells

Starling Law of the Heart

With other factors being equal, if cardiac filling increases during diastole, the volume ejected during systole also increases, SV increases nearly in proportion to increases in EDV

• Stroke volume, and therefore cardiac output, is strongly influenced by cardiac filling during diastole

Action of Sympathethetic Nerves on the Heart

• Heart is innervated by adrenergic sympathetic fibers

• When active, sympathetic nerves release norepinephrine on cardiac cells

• Norepinephrine interacts with B1-adrenergic receptors on cardiac muscle cells

  • Increases HR

  • Increases the action potential conduction velocity

  • Increases the force of contraction and rates of contraction and relaxation

• Overall, sympathetic activation acts to increase cardiac pumping

Action of the Parasympathetic Nerves on the Heart

• Cholinergic parasympathetic fibers travel to the heart via the vagus nerve and innervate the SA node, the AV node, and the atrial muscle

  • When active, parasympathetic nerves release acetylcholine on cardiac muscle cells

  • Acetylcholine interacts with muscarinic receptors on cardiac muscle cells

    • Decreases the HR (SA node)

    • Decreases the action potential velocity (AV node)

    • May also decrease the force of contraction of atrial (not ventricular) muscle cells

  • Overall, parasympathetic activation acts to decrease cardiac pumping

Five Factors Essential to Proper Ventricular Pumping Action

• The contractions of individual cardiac muscle cells must occur at regular intervals and be synchronized (not arrhythmic)

• The valves must open fully (not stenotic)

• The valves must not leak (not insufficient of regurgitant)

• The muscle contractions must be forceful (not failing)

• The ventricles must fill adequately during diastole

Arteries

• Thick-walled

• Contain some smooth muscle and a large component of elastin and collagen fibers

• Can expand under increased pressure to accept and temporarily store some of the blood ejected by the heart during diastole and then, by passive recoil, supply this blood to the organs downstream during diastole

• Arteries branch and although individual vessels get progressively smaller, the total cross-sectional area available for blood flow within the arterial system increases to several fold greater than the aorta

• Often referred to as conduit vessels because they have relatively low and unchanging resistance to flow

Arterioles

• Thicker walls with more smooth muscle and less elastic material

• Due to muscle, diameters can be actively changed to regulate the blood flow through peripheral organs

• Despite small size, arterioles are so numerous that in parallel, their collective cross-sectional area is much later than that at any level in arteries

• Often referred to as resistance vessels because of high and changeable resistance, with regulates peripheral blood flow through individual organs

Capillaries

• Smallest vessels in vasculature

• Walls consists of a single layer of endothelial cells that separates the blood from the interstitial fluid by only 1 um

• Contain no smooth muscle so lack the ability to change their diameters actively

• So numerous that the total collective cross-sectional area of all the capillaries in systemic organs is more than 1000 times that of the root of the aorta

• Viewed as the exchange vessels of the cardiovascular system

Veins

• Thin walls in proportion to diameters

• Contain smooth muscle and diameters can actively change

• Very distensible so diameters change passively in response to small changes in transmural distending pressure

• Have one-way valves that prevent reverse flow

• Peripheral venules and veins normally contain more than 50% of the total blood volume

• Thought of as capacitance vessels

• Changes in venous volume greatly influence cardiac filling and therefore cardiac pumping so play an important role in controlling cardiac output

Effect of Sympathetic Nerves on Blood Flow through Vascular Beds

• Blood flow through vascular beds is influenced by changes in activity of sympathetic nerves innervating arterioles

  • Nerves release norepinephrine that interacts with a-adrenergic receptors on the smooth muscle cells to cause contraction and arteriolar constriction

  • Reduction in arteriolar diameter increases vascular resistance and decreases blood flow

  • Most important means of reflex control of vascular resistance and organ blood flow

What affects arteriolar smooth muscle?

Arteriolar smooth muscle is responsive to changes in local chemical conditions and increased tissue metabolic rate leads to arteriolar dilation and increased tissue blood flow

Effect of Sympathetic Nerves on Venules and Veins

• Venules and veins are innervated by sympathetic nerves and smooth muscle constricts when these nerves are activated

  • Increased sympathetic nerve activity is accompanied by decreased venous volume

  • Venous constriction decreases cardiac filling and therefore cardiac output

Hematocrit

Fraction of blood volume occupied by cells

Hematocrit = cell volume/total blood volume

What are the 3 formed elements in the blood and what are their functions?

Red cells - carry oxygen from the lungs to other tissues by binding oxygen to hemoglobin

White cells - immune function

Platelets - clotting

Plasma

• Liquid component of blood

• Inorganic electrolytes are the most concentrated solutes in plasma

  • Sodium and chloride are the most abundant and are responsible for plasma's osmolarity of ~300 mOsm/L

• Contains many different proteins: albumins, globulins, fibrinogen

  • Do not readily cross capillary walls

  • Plasma concentrations are much higher than concnetration in interstitial fluid

  • Albumin most abundant

• Serves as the vehicle for transporting nutrients and waste products

  • Contains many small organic molecules such as glucose, amino acids, urea, creatinine, and uric acid

Serum

Fluid obtained from a blood sample after its allowed to clot

• Identical to plasma except it contains none of the clotting proteins

Pulmonary Circulation

Right heart pump and lungs

Systemic Circulation

Left heart pump supplying blood to systemic organs

Are the pulmonary and systemic circulations arranged in parallel or series?

Series, so right and left hearts must pump an identical volume of blood per minute (cardiac output)

Are organs arranged in parallel or series?

• Most systemic organs are arranged in parallel within the cardiovascular system

  • Nearly all systemic organs receive blood of identical composition

  • Flow through any one of the systemic organs can be controlled independently of the flow through the other organs

Blood Conditioning Organs

Kidneys, skin, large abdominal organs

Can withstand a temporary severe reduction in blood flow because the amount of cardiac output they receive greatly exceeds the amount necessary to supply the nutrient needs of the tissue

Organs in Which Blood Flow Solely Supplies the Metabolic Needs of the Tissue

Brain, heart muscle, skeletal muscle

Do not tolerate blood flow interruptions well

• Unconsciousness can occur within a few seconds after the stoppages of cerebral flow and permanent brain damage can occur in 4 minutes without flow

• Heart muscle consumes approximately 75% of the oxygen supplied to it and the heart's pumping ability begins to deteriorate within beats of a coronary flow interruption

How do cardiac muscle cell action potentials differ from skeletal muscle cells?

They can be self-generating

They are conducted directly from cell to cell

They have long duration

How do ions move in and out of cells to make transmembrane potentials?

Ions are very insoluble in lipids so they cannot pass into or out of a cell through the lipid bilayer of the membrane but rather cross via protein structures embedded in the lipid cell wall

• Ion channels

  • Responsible for resting membrane potential and for rapid changes in membrane potential that constitute the cardiac cell action potential

• Ion exchangers

• Ion pumps

How do concentration differences generate an electrical potential across a cell membrane?

• K+ more concentrated inside the cell so K+ diffuses out of the cell

• Negative charges, such as protein anions, cannot leave the cell because membrane isn't permeable to them

• K+ efflux makes cytoplasm at the inside surface of the cell membrane more negative and the interstitial fluid just outside the cell membrane more positive

• K+ is attracted to negative charge so electrical potential created across the membrane that tends to attract it back into the cell

Equilibrium Potential

The electrical forces tending to pull an ion into the cell exactly balance the concentration forces tending to pull the ion out so there is no net movement of the ion

Equilibrium Potential for Potassium

-90 mV

Equilibrium Potential for Sodium

+70 mV

How does membrane potential reflect a membrane’s relative permeability to various ions?

• Cell membranes are never permeable to just one ion so the membrane potential will lie somewhere between the equilibrium potential of the ions its permeable to, membrane potential will be closer to the ion it is more permeable to

• Under resting conditions, most heart muscle cells have membrane potentials that are quite close to the potassium equilibrium potential

Action Potential

Result of large, rapid, and transient changes in the ionic permeability of the cell membrane that are triggered by an initial small, localized depolarization and then propagated over the entire cell membrane

Fast Response Action Potentials

• From ordinary cardiac muscle cells

• Characterized by:

  • A rapid depolarization (phase 0) with a substantial overshoot (positive inside voltage)

  • A rapid reversal of the overshoot potential (phase 1)

  • A long plateau (phase 2)

  • A repolarization (phase 3) to a stable, high (large negative) resting membrane potential (phase 4)

Slow Response Action Potentials

• From cardiac pacemaker type cells

• Characterized by a slower initial depolarization phase, a lower amplitude overshoot, a shorter and less stable plateau phase, and a repolarization to an unstable, slowly depolarizing "resting" potential

• Unstable resting potential in pacemaker cells with slow-response action potentials is referred to as phase 4 depolarization, diastolic depolarization, or pacemaker potential

  • Cells usually found in the SA and AV nodes

When are the refractory periods of the cardiac cell electrical cycle?

• Cells are in an absolute refractory state during most of the action potential - they cannot be stimulated to fire another action potential

• Near the end of the action potential, membrane is relatively refractory - can be re-excited only by a larger than normal stimulus

• Immediately after the action potential, the membrane is transiently hyperexcitable - "vulnerable" or "supranormal" period

Threshold Potential

Membrane potential that when depolarized to, results in major rapid alterations in permeability of the membrane to specific ions

What are 3 mechanisms that contribute to the slow depolarization of the membrane observed during the diastolic interval in pacemaker cells?

• Progressive decrease in the membrane's permeability to K+ during the resting phase

• Permeability to Na+ increases slowly

• Slight increase in the permeability of the membrane to calcium ions late in diastole, resulting in an inward movement of the positive charged ions and contributes to diastolic depolarization

These mechanisms result in a specific current that occurs during diastole called the i-funny current

Phase 0

• Rapid rising phase of fast-response action potential is a result of a sudden increase in Na+ permeability

  • Produces fast inward current of Na+

  • Causes membrane potential to move rapidly toward the sodium equilibrium potential

  • Short lived

Phase 1

Very brief increase in potassium permeability occurs that allows a transient outward-going potassium current (iTo) and results in a small non-sustained repolarization after the peak of the action potential

Phase 2

• Prolonged depolarization plateau state is accomplished by interactions of two separate processes

  • Sustained reduction in K+ permeability

  • A slowly developed and sustained increase in the membrane's permeability to Ca2+

  • Under certain conditions, the electrogenic action of a Na+-Ca2+ exchanger may contribute to maintenance of the plateau phase of the cardiac action potential

Initial Depolarization in Slow-Response Action Potentials

Initial fast inward current is small or absent in cells that have slow-response action potentials

• Initial depolarization phase is primarily a result of an inward movement of Ca2+ potentials

Phase 3

In both types of cells, the membrane is repolarized to its original resting potential as the K+ permeability increases to its high resting value and the Ca2+ and Na+ permeabilities return to their low resting values

What are the conformational states that ion channels exist in?

Open

Closed

Inactivated

Voltage Gated Channels

Probability of being open varies with membrane potential

Ligand-Gated Channels

Activated by certain neurotransmitters or other specific signal molecules

K+ Channel (Inward Rectifier), K_ir Current

iK1

K+ Channel (Inward Rectifier), K_ir Gating Mechanism

Voltage

K+ Channel (Inward Rectifier), K_ir Functional Role

Maintains high K+ permeability during phase 4

Its decay contributes to diastolic depolarization

Its suppression during phases 0-2 contributes to plateau

Na+ Channel (Fast) Nav 1.5 Current

iNa

Na+ Channel (Fast) Nav 1.5 Gating Mechanism

Voltage

Na+ Channel (Fast) Nav 1.5 Functional Roles

Accounts for phase 0 of action potential

Inactivation may contribute to phase 1 of action potential

K+ Channel (transient outward), K_to Current

iTo

K+ Channel (transient outward), K_to Gating Mechanism

Voltage

K+ Channel (transient outward), K_to Functional Role

Contributes to phase 1 of action potential

Ca2+ Channel (Slow Inward, L Channels) Cav 1.2 Current

iCa

Ca2+ Channel (Slow Inward, L Channels) Cav 1.2 Gating Mechanism

Both

Ca2+ Channel (Slow Inward, L Channels) Cav 1.2 Functional Roles

Contributes to phase 2 of action potential

Inactivation may contribute to phase 3 of action potential

Is enhanced by sympathetic stimulation and B-adrenergic agents

K+ Channels (Delayed Rectifier), K_s, K_r, K_ur Current

iK

K+ Channels (Delayed Rectifier), K_s, K_r, K_ur Gating Mechanism

Voltage

K+ Channels (Delayed Rectifier), K_s, K_r, K_ur Functional Roles

Causes phase 3 of action potential

Is enhanced by increased intracellular Ca2+

K+ Channel (ATP-Sensitive) Current

iKATP

K+ Channel (ATP-Sensitive) Gating Mechanism

Ligand

K+ Channel (ATP-Sensitive) Functional Roles

Increases K+ permeability when [ATP] is low

K+ Channel (Acetylcholine Activated) Current

iKACh

K+ Channel (Acetylcholine Activated) Gating Mechanism

Ligand

K+ Channel (Acetylcholine Activated) Functional Roles

Responsible for effects of vagal stimulation

Decreases diastolic depolarization (and the heart rate)

Hyperpolarizes resting membrane potential

Shortens phase 2 of the action potential

Na+, Ca2+, K+ (Pacemaker Current via HCN Channel) Current

i_f (“funny)

Na+, Ca2+, K+ (Pacemaker Current via HCN Channel) Gating Mechanism

Both

Na+, Ca2+, K+ (Pacemaker Current via HCN Channel) Functional Roles

Is activated by hyperpolarization and cyclic nucleotides and contributes to the diastolic depolarization

Is enhanced by sympathetic stimulation and B-adrenergic agents

Is suppressed by vagal stimulation

Activation and Inactivation Gates of Channels

• Both gates respond to changes in membrane potential but with different voltage sensitivities and time courses

• Inactivation gates of Na+ channels remain closed during the plateau phase and the remainder of the action potential, inactivating the action potential

• Sustained sodium channel inactivation, combined with activation of calcium channels and delay in opening of potassium channels accounts for the long plateau phase and long cardiac refractory period, which lasts until the end of phase 3

• With repolarization, both gates of the sodium channel return to their original position and the channel is ready to be reactivated by a subsequent depolarization

Factors other than Membrane Voltage that Influence Membrane Ionic Permeability and Operation of Ion Channels

• High intracellular Ca2+ concentration during systole contributes to activation of certain K+ channels and increases the rate of repolarization

• Sympathetic and parasympathetic input can influence some voltage-gated channels and cause activation or suppression of ligand-gated channels

• Mechano-gated and mechano-modulated channels may be activated by myocyte stretch or myocyte volume changes

Depolarization Beyond Rising Phase of the Action Potential in Fast-Response Action Potential vs Slow-Response Action Potential

• Slow-response action potential differs from the fast-response action potential primarily because of the lack of a strong activation of the fast Na+ channel at its onset

  • Depolarization beyond threshold during the rising phase of the action potential in "pacemaker" cells is slow and primarily caused by the influx of Ca2+ through slow L-type channels

How is rapid depolarization vs slow depolarization initiated in cardiac cells?

• All cardiac cells are capable of having fast-type or slow-type action potentials

  • Rapid depolarization to threshold potential is usually forced on a cell by the occurrence of an action potential in an adjacent cell

  • Slow depolarization to threshold occurs when a cell itself spontaneously and gradually loses its resting polarization, which usually happens only in the SA or AV node

How do cardiac muscle cells connect?

• Cardiac muscle cells branch and connect end-to-end with neighboring cells in cells called intercalated disks which contain

  • Firm mechanical attachments between adjacent cell membranes by adherins in desmosomes

  • Low-resistance electrical connections between adjacent cells through channels formed by connexin in gap junctions