CIRCULATORY SYSTEM

PHYSIOLOGY

CIRCULATORY SYSTEM
The circulatory system - is an organ system that passes nutrients gases, hormones, waste products blood cells, etc. to and from cells to maintain homeostasis - composed of the cardiovascular system, which distributes blood, and the lymphatic system

The main components of the human cardiovascular system are: heart, blood, blood vessels: arteries, arterioles, capillaries, venules and veins heart is the pump, arteries are conduits, arterioles are resistance vessels, capillaries are exchange sites, veins are mainly blood reservoirs.

CIRCULATORY SYSTEM

CARDIOVASCULAR SYSTEM
THE HEART muscular pump whose main function is to propel blood throughout the body lies between the lungs and just to the left of the middle of the chest cavity has a mass of between 250 and 350 grams is about the size of a fist

THE HEART
has four chambers that are enclosed by thick, muscular walls: the right and left atria the right and left ventricles the interatrioventricular septum separates the left atrium and ventricle from the right atrium and ventricle, dividing the heart into two functionally separate and anatomically distinct units

THE HEART
Heart is enclosed in a double-walled protective sac, the pericardium The wall of the human heart is composed of three layers: - the epicardium, the outer layer - or visceral pericardium (it is also the inner wall of the (serous) pericardium). - the myocardium, the middle layer - composed of muscle which contracts. - the endocardium, the inner layer - is in contact with the blood that the heart pumps[. It merges with the inner lining (endothelium) of blood vessels and covers heart valves

THE HEART
the pericardium double membrane contains a small amount of the pericardial fluid which nourishes the heart and prevents from shocks. - protects the heart, - anchors its surrounding structures - prevents overfilling of the heart with blood. - Its inner layer provides a smooth lubricated sliding surface within which the heart can move in response to its own contractions and to movement of adjacent structures such as the diaphragm and lungs.

 The endocardium - innermost layer of tissue that lines the chambers of the heart primarily made up of endothelial cells -

THE HEART

part of the myocardial function control systems controls the development of the heart in the embryo as well as in the adult, for example during hypertrophy. regulate contractility and electrophysiological environment of the cardiomyocyte act as a blood-heart barrier (analogous to the bloodbrain barrier), controlling the ionic composition of the extracellular fluid in which the cardiomyocytes bathe

 the myocardium

THE HEART

-composed of highly organized cardiac muscle cells connected together to form a syncytium with tight electrical and mechanical connections - classified as a striated muscle with specificities in terms of organization, electrical and mechanical coupling and mechanisms to regulate the force of contraction. -cardiac muscle cells importance lie in heart continuous pumping activity Structure of a cardiac muscle cell. (MF)- myofibrils
(Mit)- mitochondria (ID)- intercalated disks (Nu)nucleus (BV)- blood vessel (ECF)- extracellular fluid (SL)- sarcolemma (TT)- T-tubules.

THE HEART
Muscle cells are composed of tubular myofibrils surounded by the sarcoplasmic reticulum (internal network of membranes whose terminal regions abut the T tubule-invaginations of sarcolemma positioned at the Z lines ) or lie just below the sarcolemma
Skeletal muscle cell ultrastructure: 1) myofibrils 2) sarcoplasmic reticulum 3). 4) T-tubules. 5) surface membrane .6) mitochondria

THE HEART
- each myofibril is surrounded by elements of the SR with their terminal cisterns. - T-tubules. are invaginations of the surface membrane that form a network of tubules extending into the center of the cell. - the lumen of the T-tubule is continuous with the extracellular space - numerous mitochondria lie between myofibrils

THE HEART
Myofibrils are composed of repeating sections of sarcomeres, the contractil units of the muscle cell limited by two Z membranes Sarcomeres are composed of long, fibrous proteins that slide past each other when the muscles contract and relax. Myofibrils are composed of arrays of thick and thin filaments. -Z lines are points of attachment of thin filaments - Thin filaments are composed of actin, tropomyosin and troponin and extend into the A band -A band is composed of thick filaments with some overlap of thin filaments -thick filaments are composed of myosin and extend from the centre of the sarcomere toward Z lines

THE HEART
Thin Filaments in Skeletal Muscle Are Composed of Major Proteins:
Actin is a globular protein (G-actin) with a molecular weight of 41,700 daltons made of G-actin monomers that aggregate to form strands resembling a string of pearls. The thin filament consists primarily of two helical strands of G-actin wound around each other Nebulin, 600-kDa protein molecule, runs along the thin filament and forms a template that limits the length of the actin filaments. Alfa-actinin, anchors actin filaments on Z line Tropomyosin and troponin, are regulatory proteins from the thin filament Tropomyosin , a long, rod-shaped protein dimer lies along both sides of the thin filament in grooves formed by the two strands of actin molecules. Each tropomyosin molecule binds to seven actin monomers in one of the strands. Troponin, which is bound to tropomyosin, is a complex of three proteins: troponin T (TnT), troponin C (TnC), and troponin I (TnI). Tropomyosin and troponin are involved in the calcium (Ca2+)-dependent regulation of skeletal muscle contraction Actin Tropomodulin, at the end of actin filaments control the length of thin filaments

THE HEART
Thick Filaments are composed mostly of myosin myosin - a large protein consisting of two heavy chains and two pairs of different light chains-a myosin essential light chain and a myosin regulatory light chain (RLC). - It has a long, rod-like tail with two globular heads - the rod-like portion of the molecule contains an "arm" adjacent to each globular head. - at each end of the arm is a flexible region that acts as a hinge, allowing rotation at that point.

THE HEART
- many myosin molecules align to form a thick filament - the tail regions of the molecules are bundled to form the body of the thick filament. - the globular heads and arm regions project out from the bundle. - the heads of the myosin molecules can bind to the thin filaments to form cross-bridges between the two filaments. T - the myosin heads in each half of the thick filament are oriented in opposite directions; the heads are not present in the central region Titin, large elastic protein, - tether myosin to the Z lines preventing overstretching of sarcomeres, - participate in cell signaling modulating protein synthesis, - might contribute to increase force upon strech

the heads of the myosin molecules can bind to the thin filaments to form cross-bridges between the two filaments. T

HEART CHAMBERS
Cardiac atria
- in the upper part of the heart - receive the blood entering the heart - the interatrial septum divides the atria - small chambers - thin muscular walls - operate more as passive reservoir. - they contract enhancing ventricular filling to additional 15 % of total ventricular filling - Internally, there is the rough musculae pectinati and crista terminalis which acts as a boundary inside the atrium and the smooth walled part derived from the sinus venosus Right atrium receives deoxygenated systemic venous returned from inferior and superior vena cava and coronary sinus Left atrium receives oxygenated blood from the lungs via left and right pulmonary veins

HEART CHAMBERS
Atrial function:
- prevent circulatory inertia and - allow uninterrupted venous flow to the heart becouse: (1) there are no atrial inlet valves to interrupt blood flow during atrial systole. (2) the atrial systole contractions are incomplete and thus do not contract to the extent that would block flow from the veins through the atria into the ventricles. During atrial systole, blood not only empties from the atria to the ventricles, but blood continues to flow uninterrupted from the veins right through the atria into the ventricles. (3) the atrial contractions must be gentle enough so that the force of contraction does not exert significant back pressure that would impede venous flow. (4) the "let go" of the atria must be timed so that they relax before the start of ventricular contraction, to be able to accept venous flow without interruption

HEART CHAMBERS
Cardiac ventricles
- pump blood out of the heart - the interventricular septum divides the ventricles - two large chambers collect blood from atria and expel it towards the peripheral beds within the body and lungs - have thicker walls than atria and generate higher blood pressures - the left ventricle has thicker walls (3-4X)than the right because it needs to pump blood to most of the body while the right ventricle fills only the lungs.

-the right ventricle receives blood through the right atrium and pumps it into the pulmonary circulation through the pulmonary artery, - the left ventricle receives blood through the left atrium and pumps it into the systemic circulation through the aorta (systemic circulation).

Cardiovascular system-heart chambers

the performance of the ventricles are measured with several volumetric parameters, including end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV)and ejection fraction(Ef). Typical value Normal range end-diastolic volume (EDV) 120 mL (65240 ml) end-systolic volume (ESV) 50 ml (16143ml) stroke volume (SV) 70 mL (55100 ml) ejection fraction (Ef) 58% (5570% ) cardiac output (CO) 5.25 l/minute 4.08.0 L/min

HEART VALVES
Heart valves are attached to the chordae tendinae (literally the heartstrings), which anchors the valves to the papilla muscles of the heart atrioventricular valves separate atria, from the ventricles through : - tricuspid valve between the right atrium and the right ventricle, -mitral valve between the left atrium and the left ventricle semilunar valves separate ventricles from the blood vessels through : -pulmonary valve between the right ventricle and the pulmonary artery -aortic valve between the left ventricle and aorta

Heart valves
Heart valves functions Allow blood flow in one direction only Open passively when upstream pressure exceeds downstream pressure Close passively when downstream pressure exceeds upstream pressure The movement of valve leaflets can be detected by echocardiography Their closure makes an important component of the heart sounds

ELECTRICAL PROPERTIES OF HEART MUSCLE CELLS

Biologically important ions (e.g., Na+, K+,, Ca2+, Cl-) typically are asymmetrically distributed across a biological membrane. This implies that a concentration gradient exists for each type of ion across the membrane. Movement of ions (which carry electrical charge) across a membrane changes the electrical potential across the membrane. a cell membrane is permeable to multiple ionic species, each of which will have a flux across the membrane. The steady-state resting membrane potential Vm of a cell is achieved when all the ionic fluxes balance each other so that no net movement of ionic charges across the membrane occurs. A cell can change its Vm by controlling the relative permeabilities of the cell membrane to certain ions (principally Na+, K+, Ca2+, and Cl-). The membrane potential (Vm) for a cell is defined as the electrical potential inside the cell measured relative to the electrical potential outside

Extracellular Fluid Na+ (mEq/L) K+ (mEq/L) Cl (mEq/L HCO3 (mEq/L) Ca++ (mmol/L)* Pi (mmol/L)* 135-147 3.5-5.0 95-105 22-28 2.1-2.8 (total) 1.1-1.4 (ionized) 1.0-1.4 (total) 0.5-0.7 (ionized)

Extracellular Fluid 10-15 120-150 20-30 12-16 107 (ionized) 0.5-0.7 (ionized)

RESTING MEMBRANE POTENTIAL

The resting cell membrane has relatively high permeability to K+ and much less permeability to Na+ and Ca++ Given the existing chemical gradient for K+ and Vm, K+ tends to diffuse from the inside to the outside of the cell. Any flux of K+ that occurs at the resting membrane potential takes place mainly through specific K+ channels. Several types of K+ channels exist in cardiac cell membranes. Opening and closing of some of these channels are regulated by Vm, whereas others are controlled by a chemical signal (e.g., the extracellular acetylcholine concentration). The specific K+ channel through which K+ passes during resting phase is a voltage-regulated channel that conducts the inwardly rectifying K+ current. This current is symbolized iK1 The Vm depend on conductance of the membrane to a particular ion (determined by the number of ion channels in the membrane and the amount of time each channel is in open stat) and the intracellular and extracellular concentrations of K+, Na+, and other ions.

RESTING MEMBRANE POTENTIAL

In a resting cardiac cell, conductance to K+ (gK) is about 100 times greater than conductance to Na+ (gNa). As a result, alterations in extracellular [K+] can significantly change Vm, with hypokalemia causing hyperpolarization and hyperkalemia causing depolarization. In contrast, because gNa is so small in the resting cell, changes in [Na+]o do not significantly affect Vm.

ACTION POTENTIALS (AP)

Action potentials are caused by a sudden selective alteration in the permeability of the membrane to small ions There are two main types of AP - the fast response AP, occurs in normal atrial and ventricular myocytes and in the specialized conducting fibers (Purkinje fibers of the heart) - the slow response AP, occurs in the sinoatrial(SA)node cells, (the natural pacemaker region of the heart), and in the atrioventricular(AV)node cells, (the specialized tissue that conducts the cardiac impulse from the atria to the ventricles).

ACTION POTENTIALS (AP)

- differences between the electrical properties of the fast response and slow response cells AP: The resting membrane potential (phase 4) of the fast-response cells is considerably more negative than that of the slow response cells. the slope of the upstroke (phase 0), the amplitude of the action potential, and the overshoot are greater in the fastresponse In slow-response cardiac tissue, the AP is propagated more slowly and conduction is more likely to be blocked than in fast-response cardiac tissue (they depend on AP amplitude and the steepness of the upstroke) The slow-response cells lack the early repolarization phase (phase 1)

ACTION POTENTIALS (AP)

the fast response AP is divided into five phases. -phase 0 depolarisation - rapid upstroke of the action potential -phase 1 - the upstroke is followed by a brief period of partial, early repolarization - phase 2 - the plateau that persists for about 0.1 to 0.2 second. - phase 3 - membrane repolarizes until the resting state of polarization Final repolarization (phase 3) develops more slowly than depolarization (phase 0) - phase 4 - resting state of polarization is again attained. - The various phases of the cardiac action potential are associated with changes in cell membrane permeability, mainly to Na+, K+, and Ca+ + ions. - Changes in cell membrane permeability alter the rate of movement of these ions across the membrane and thereby change the membrane voltage (Vm). - These changes in permeability are accomplished by the opening and closing of ion channels that are specific for individual ions

 Any stimulus that abruptly depolarizes Vm to a critical value (called the threshold) elicits an action potential. The rapid depolarization (phase 0) is related almost exclusively to the influx of Na+ into the myocyte as a result of a sudden increase in gNa. The action potential amplitude (the potential change during phase 0) is dependent on [Na+]o. When the resting membrane potential, Vm, is suddenly depolarized from 90 mV to the threshold level of about 65 mV, the cell membrane properties change dramatically. Na+ enters the myocyte through specific fast voltage-activated Na+ channels that exist in the membrane. The Na+ channels open very rapidly or activate (in about 0.1 msec), thereby resulting in an abrupt increase in gNa. However, once opened, the Na+ channels inactivate (time course 1 to 2 msec), and gNa rapidly decreases . The Na+ channels remain in the inactivated state until the membrane begins to repolarize. With repolarization, the channel transitions to the closed state, from which it can then be reopened by another depolarization of Vm to the threshold.

FAST-RESPONSE ACTION POTENTIALS Genesis of the Upstroke (Phase 0)

FAST-RESPONSE ACTION POTENTIALS Genesis of the Upstroke (Phase 0)

These properties of the Na+ channel underlie the basis of the action potential refractory period. When the Na+ channels are in the inactivated state, they cannot be reopened, and another action potential cannot be generated. During this period the cell is said to be in the effective refractory period. This prevents a sustained, tetanic contraction of cardiac muscle, which would retard ventricular relaxation and therefore interfere with the normal intermittent pumping action of the heart. As the cell repolarizes (phase 3), the inactivated channels begin to transition to the closed state. During this period, called the relative refractory period, another action potential can be generated, but it requires a larger than normal depolarization of Vm. Only when Vm has returned to the resting level (phase 4) all the Na+ channels closed and thus able to be reactivated by the normal depolarization of Vm. When [Na+]o is decreased, the amplitude of the action potential decreases, and when [Na+]o is reduced from its normal value of about 140 mEq/L to about 20 mEq/L, the cell is no longer excitable.

FAST-RESPONSE ACTION POTENTIALS Genesis of Early Repolarization (Phase 1)

phase 1 is an early, brief period of limited repolarization that results in the notch between the end of the upstroke and the beginning of the plateau Repolarization is brief because of activation of a transient outward current (ito) carried mainly by K+. Activation of K+ channels during phase 1 causes a brief efflux of K+ from the cell because the cell interior is positively charged and [K+]i greatly exceeds [K+]o. The cell is briefly and partially repolarized as a result of this transient efflux of K+. The size of the phase 1 notch varies among cardiac cells. It is prominent in myocytes in the epicardial and midmyocardial regions of the left ventricular wall and in ventricular Purkinje fibers. the notch is negligible in myocytes from the endocardial region of the left ventricle because the density of ito channels is less in these cells.

FAST-RESPONSE ACTION POTENTIALS Genesis of the Plateau (Phase 2)

During the action potential plateau, Ca+ + enters myo-crdial cells through calcium channels that activate and inactivate much more slowly than the fast Na+ channels do. During the flat portion of phase 2 this influx of Ca+ + is counterbalanced by the efflux of K+. K+ exits through channels that conduct mainly the ito, iK, and iK1 currents. The ito current is responsible for phase 1, but it is not completely inactivated until after phase 2 has expired. Ca+ + enters the cell via voltage-regulated Ca++ channels, which are activated as Vm becomes progressively less negative during the action potential upstroke. Two types of Ca+ + channels (L type and T type) have been identifi ed in cardiac tissue. L-type channels are so designated because once open they inactivate slowly and provide a long-lasting Ca+ + current. They are the predominant type of Ca+ + channel in the heart, and they are activated during the action potential upstroke when Vm reaches about 20 mV. L-type channels are blocked by Ca+ +channel antagonists such as verapamil, amlodipine, and diltiazem

FAST-RESPONSE ACTION POTENTIALS Genesis of the Plateau (Phase 2)

T-type (or transient) Ca+ + channels are much less abundant in the heart. They are activated at more negative potentials (about 70 mV) and more quickly than L-type channels are. Opening of Ca+ + channels results in an increase in Ca+ + conductance (gCa) and current (iCa) soon after the action potential upstroke. Because [Ca+ +]i is much less than [Ca+ +]o the increase in gCa promotes the influx of Ca+ + into the cell throughout the plateau. This Ca+ + influx during the plateau is involved in excitation-contraction coupling, Various neurotransmitters and drugs may substantially influence gCa. - the adrenergic neurotransmitter norepinephrine, the -adrenergic receptor agonist iso-proterenol, and various other catecholamines enhance gCa, Enhancement of gCa by catecholamines is the principal mechanism by which they enhance cardiac muscle contractility - the parasympathetic neurotransmitter acetylcholine decreases gCa..

FAST-RESPONSE ACTION POTENTIALS Genesis of the Plateau (Phase 2)

During the plateau (phase 2) of the action potential, the concentration gradient for K+ across the cell membrane is virtually the same as it is during phase 4; However, Vm is now positive. Therefore, there is a large gradient that favors efflux of K+ from the cell. If gK were the same during the plateau as it is during phase 4, efflux of K+ during phase 2 would greatly exceed the infl ux of Ca+ +, and a sustained plateau could not be achieved. However, as Vm approaches and then attains positive values near the peak of the action potential upstroke, gK suddenly decreases The diminished K+ current associated with the reduction in gK prevents excessive loss of K+ from the cell during the plateau.

FAST-RESPONSE ACTION POTENTIALS Genesis of the Plateau (Phase 2)

This reduction in gK at both positive and low negative values of Vm is called inward rectification. Inward rectification is a characteristic of several K+ currents, including the iK1 current. For these channels, large K+ currents flow at negative values of Vm (i.e., gK is large). However, when Vm is near 0 mV, or positive, as occurs during the plateau (phase 2), little or no K+current flows (i.e., gK is low). the substantial gKt hat prevails during phase 4 of the cardiac action potential is largely due to the iK1 channels, but current through these channels is greatly diminished during the plateau .

FAST-RESPONSE ACTION POTENTIALS Genesis of the Plateau (Phase 2)

Other K+ channels play a role in phase 2 of the action potential. These are characterized as delayed rectifier(iK) channels. activation of these channels tends to increase gK very gradually during phase 2. These channels play only a minor role during phase 2, but they contribute to the process of final repolarization (phase 3) Two types of iK channels exist, dependng on their rates of activation. The more slowly activating channel is designated the iKs channel, whereas the more rapidly activating channel is designated the iKr channel . The duration of the action potential in myocytes in various regions of the ventricular myocardium is determined in part by the relative distributions of these iKr and iKs channels.

FAST-RESPONSE ACTION POTENTIALS Genesis of Final Repolarization (Phase 3)

starts at the end of phase 2, when efflux of K+ from the cardiac cell begins to exceed influx of Ca++. at least three outward K+ currents (ito, iK, and iK1) contribute to the final repolarization (phase 3) of the cardiac cell The transient outward (ito) and the delayed rectifier (iKr, iKs) currents help initiate repolarization. The inwardly rectified K+ current iK1 does not participate in the initiation of repolarization because the conductance of these channels is very small over the range of Vm values that prevail during the plateau. However, the iK1 channels contribute substantially to the rate of repolarization once phase 3 has been initiated. As Vm becomes increasingly negative during phase 3, the conductance of the channels that carry the iK1 current progressively increases and thereby accelerates repolarization

 the steady inward leak of Na+ that enters the cell rapidly during phase 0 and more slowly throughout the cardiac cycle would gradually depolarize the resting membrane voltage were it not for Na+,K+ATPase, which is located in the cell membrane . Similarly, most of the excess Ca++ ions that had entered the cell mainly during phase 2 are eliminated principally by a 3Na+-1Ca++ antiporter, which exchanges 3 Na+ ions for 1 Ca++ ion. Some of the Ca++ ions are eliminated by an ATP-driven Ca++ pump.

FAST-RESPONSE ACTION POTENTIALS Restoration of Ionic Concentrations (Phase 4)

Principal ionic currents and channels that generate the various phase in the AP in a cardiac cell:
Phase 0: the chemichal and electrostatic forces both in favour the entry of Na+ into the cell through fast Na channels. Phase 1: the chemichal and electrostatic forces both in favour the efflux of K+ through I to channels to generate early, partial repolarisation Phase 2: during the plateau, the net influx of Ca++ through Ca channels is balanced by the efflux of K+ through Ik, Ik1,Ito channels Phase 3: the chemichal forces that favour the efflux of K+ through Ik, Ik1,I o channels predominate over the electrostatic forces that favour the influx of K+ through these same channels Phase 4 the chemichal forces that favour the efflux of K+ through Ik, Ik1, Ito channels very slightly exceed the electrostatic forces that favour the influx of K+ through these same channels

SLOW-RESPONSE ACTION POTENTIALS

Certain cells in the heart, notably those in the SA and AV nodes, exhibit slowresponse action potentials. In these cells, depolarization is achieved mainly by infl ux of Ca++ through L-type Ca++ channels instead of infl ux of Na+ through fast Na+ channels. Repolarization is accomplished in these fibers by inactivation of the Ca++ channels and by the increased K+ conductance through the iK1 and iK channels the upstroke is much less steep, early repolarization (phase 1) is absent, the plateau is less prolonged and not as flat, and the transition from the plateau to the fi nalrepolarization is less distinct.