Sarcoplasmic Reticulum

6. Sarcoplasmic reticulum (SR) are small-diameter tubules in close proximity to the contractile elements. are the site of storage and release of c a ~ for < - excitation-contraction coupling. B. Steps in excitation-contraction coupling 1. The action potential spreads from the cell membrane into the T tubules. 2. During the plateau of the action potential, ca:z... conductance is increased and Ca2+ enters the cell from the extracellular fluid (inward e a ~ < current) through L-type Cau channels (dihydropyridine receptors). 3. This Ca2+ entry triggers the release of even more ca:z... from the SR ( C a ~ < - - i CaJ+ n d u release) through cau release channels (ryanodine receptors). The amount of cau released from the SR depends on the: a. amount of Cau previously stored in the SR. b. size of the inward Ca2+ current during the plateau of the action potential 4. As a result of this Ca2+ release, intracellular [ C a ~ increases. < -] 5. Cau binds to troponin C, and tropomyosin is moved out of the way, removing the inhibition of actin and myosin binding. 6. Actin and myosin bind, the thick and thin filaments slide past each other, and the myocardial cell contracts. The magnitude of the tension that develops is proportional to the intracellular [ c a ~ < - ] . 7. Relaxation occurs when Ca2+ is reaccumulated by the SR by an active Ca2+-ATPase pump, intracellular Cau concentration decreases, and Ca:z... dissociates from troponin C. C. Contractibility is the intrinsic ability of cardiac muscle to develop force at a given muscle length. is also called inotropism. is related to the intracellular CaJ+ concentration. can be estimated by the ejection fraction (stroke volume/end-diastolic volume), which is normally 0.55 (55%). Positive inotropic agents produce an increase in contractility. Negative inotropic agents produce a decrease in contractility. 1. Factors that increase contractility (positive inotropism) [see Table 3.1] a. Increased heart rate When more action potentials occur per unit time, more Ca2+ enters the myocardial cells during the action potential plateaus, more Ca2+ is stored in the SR, more Ca2+ is released from the SR, and greater tension is produced during contraction. Examples of the effect of increased heart rate are (1) positive staircase or Bowditch staircase (or treppe). Increased heart rate increases the force of contraction in a stepwise fashion as the intracellular [Caul increases cumulatively over several beats. (2) postextrasystolic potentiation. The beat that occurs after an extrasystolic beat has increased force of contraction because "extra'' ea:z... entered the cells during the extrasystole. b. Sympathetic stimulation (catecholamines) via P, receptors {see Table 3.1) increases the force of contraction by two mechanisms: (1) It increases the inward CaJ+ current during the plateau of each cardiac action potential. (2) It increases the activity of the Ca2+ pump of the SR {by phosphorylation of phospholamban); as a result, more eau is accumulated by the SR and thus, more cau is available for release in subsequent beats. c. Cardiac glycosides (digitalis) increase the force of contraction by inhibiting Na+, K+-A1Pase in the myocardial cell membrane (Figure 3.7). c e d RGURE 3.7. Stepwise explanation of how ouabain !digitalis) causes an increase in intracellular [Ca2+] and myocardial contractility. The circled numbers show the sequence of events. Myocardial cell As a result of this inhibition, the intracellular [Na+] increases, diminishing the Na+ gra- dient across the cell membrane. Na+-Ca2+ exchange (a mechanism that extrudes Ca2+ from the cell) depends on the size of the Na+ gradient and thus is diminished, producing an increase in intracellular [Ca2+], 2.. Factors that decrease contractility tnegative inotropism) [see Table 3.1] Parasympathetic stimulation (ACh) via muscarinic receptors decreases the force of contraction in the atria by decreasing the inward Ca2+ current during the plateau of the cardiac action potential. D. Length-tension relationship in the ventricles (Figure 3.8} describes the effect of ventricular muscle cell length on the force of contraction. is analogous to the relationship in skeletal muscle. 1. Preload is and-diastolic volume. which is related to right atrial pressure. When venous return increases, end-diastolic volume increases and stretches or lengthens the ventricular muscle fibers {see Frank-Starling relationship, IV D 5). 2.. Aftarload for the left ventricle is aortic pressure. Increases in aortic pressure {i.e., systemic hypertension) cause an increase in afterload on the left ventricle. ..........-~············-········...•• in:~~rc effect ...... //•' _;· . / ! / ........ ;' I : , ," ,• ~ .... ~ ~ ~ .. "' ~ -~-- .. Negative inotropic effect ....... ~ ......... .. .,. ' ,.., Right atrial pressure or end-diastolic volume FIGURE 3.8. Frank-Starling relationship and the effect of positive and negative inotropic agents. for the right ventricle is pulmonary artery pressure. Increases in pulmonary artery (i.e., pulmonary hypertension) pressure cause an increase in afterload on the right ventricle. 3. Sarcomere length determines the maximum number of crossbridges that can form between actin and myosin. determines the maximum tension, or force of contraction. 4. Velocity of contraction at a fixed muscle length is maximal when the afterload is zero. is decreased by increases in afterload. 5. Frank-Starling relationship describes the increases in stroke volume and cardiac output that occur in response to an increase in venous return or end-diastolic volume (see Figure 3.8). is based on the length-tension relationship in the ventricle. Increases in end-diastolic volume cause an increase in ventricular fiber length. which produces an increase in developed tension. is the mechanism that matches cardiac output to venous return. The greater the venous return, the greater the cardiac output. Changes in contractility shift the Frank-Starling curve upward (increased contractility) or downward (decreased contractility). a. Increases in contractility cause an increase in cardiac output for any level of right atrial pressure or end-diastolic volume. b. Decreases in contractility cause a decrease in cardiac output for any level of right atrial pressure or end-diastolic volume. E. Ventricular pressure-volume loops ~Figure 3.9) are constructed by combining systolic and diastolic pressure curves. The diastolic pressure curve is the relationship between diastolic pressure and diastolic volume in the ventricle. The systolic pressure curve is the corresponding relationship between systolic pressure and systolic volume in the ventricle. A single left ventricular cycle of contraction. ejection. relaxation. and refilling can be visualized by combining the two curves into a pressure-volume loop. 1. Steps in the cycle a. 1 -+ 2 (isovolumetric contraction). The cycle begins at the end of diastole at point 1. The left ventricle is filled with blood from the left atrium and its volume is about 140 mL (end-diastolic volume). Ventricular pressure is low because the ventricular muscle is relaxed. On excitation, the ventricle contracts and ventricular pressure increases. The mitral valve closes when left ventricular pressure is greater than left atrial pressure. Because all valves are closed, no blood can be ejected from the ventricle (isovolumetric), e:I ~ 150 3 c.~ ~CI .!!!I .g ~ c:~ 2 75 ~ ;I:: .3 4 0 0 50 100 Left ventricular volume (mL) 150 FIGURE 3.9. Left ventricular pressure-volume loop. --B A I!! ~ Q. j ;;;, .g c: ~ = j Increased ·d~ 2 ~ Increased ~~~~ aftefoad 1 __! Left ventricular volume Increased contractility . -3 ~~ I ' I : I I 4 -- c 4 i •'3 I I I }2 : 1 L-t Left ventricular volume I I I -. I ·o ~ ~~~~-- '\ \ 2 1 Left ventricular volume RGURE 3.10. Effects of changes in (A) preload, (B) afterload, and (C) contractility on the ventricular pressure-volume loop. b. 2 -+ 3 (ventricular ejection). The aortic valve opens at point 2 when pressure in the left ventricle exceeds pressure in the aorta. Blood is ejected into the aorta, and ventricular volume decreases. The volume that is ejected in this phase is the stroke volume. Thus, stroke volume can be measured graphically by the width of the pressure-volume loop. The volume remaining in the left ventricle at point 3 is end-systolic volume. c. 3 -+ 4 Usovolumetric relaxation). At point 3, the ventricle relaxes. When ventricular pressure decreases to less than aortic pressure, the aortic valve closes. Because all of the valves are closed again, ventricular volume is constant (isovolumetric) during this phase. d. 4 -+ 1 (ventricular filling). Once left ventricular pressure decreases to less than left atrial pressure, the mitral valve opens and filling of the ventricle begins. During this phase, ventricular volume increases to about 140 mL (the end-diastolic volume). 2. Changes in the ventricular pressure-volume loop are caused by several factors (Figure 3.10). a. Increased preload (see Figure 3.10A) refers to an increase in end-diastolic volume and is the result of increased venous return (e.g., increased blood volume or decreased venous capacitance) causes an increase in stroke volume based on the Frank-Starling relationship. The increase in stroke volume is reflected in increased width of the pressure-volume loop. b. Increased afterload (see Figure 3.10B) refers to an increase in aortic pressure. The ventricle must eject blood against a higher pressure, resulting in a decrease in stroke volume. The decrease in stroke volume is reflected in decreased width of the pressure-volume loop. The decrease in stroke volume results in an increase in end-systolic volume. c. Increased contractility (see Figure 3.10C) The ventricle develops greater tension than usual during systole, causing an increase in stroke volume. The increase in stroke volume results in a decrease in end-systolic volume. F. Cardiac and vascular function curves (Figure 3.11) are simultaneous plots of cardiac output and venous return as a function of right atrial pressure or end-diastolic volume. 1. The cardiac function (cardiac output) curve depicts the Frank-Starling relationship for the ventricle. shows that cardiac output is a function of end-diastolic volume.