L 18 cardiac contractility notes.pdf

Dr. Seham Zakaria L 18; Myocardial contractility Objectives: Relate the molecular basis of contraction to the structure of cardiac muscle Describe the excitation contraction coupling. Correlate the types of heart contraction to its pumping action. Definition: It is the ability of the cardiac muscle...

Dr. Seham Zakaria L 18; Myocardial contractility Objectives: Relate the molecular basis of contraction to the structure of cardiac muscle Describe the excitation contraction coupling. Correlate the types of heart contraction to its pumping action. Definition: It is the ability of the cardiac muscle to contract The contraction of cardiac chamber is called systole and its relaxation is called diastole. The fundamental contractile unit in both skeletal and cardiac muscle is the sarcomere. These units are about 2 μm long and are defined at each end by the Z line. Attached to the Z lines are the thin filaments. The thin filaments are made from actin which in turn consist of G-actin monomers joined together, in a structure that resemble a helical string of beads, to form the thin filament. These actin thin filaments are arranged in a parallel sandwich structure with the protein myosin (thick filament). The thick filaments are made from Myosin that is in the form of two heavy chains wrap around each other to form a double helix (the tail of the myosin molecule). One end of each of these chains is folded into a globular polypeptide structure called a myosin head. two free heads at one end of the double-helix myosin molecule. The protruding arms and heads together are called crossbridges. The myosin heads has ATPase acivity. The arrangement of the actin and myosin protein creates a striated appearance in which the A band is generated by the myosin filaments and the I band is composed mainly of actin. Fig. 1 Arrangement of actin (thin filament) and myosin (thick filament) within the contractile unit of cardiac muscle, the sarcomere. 1 Dr. Seham Zakaria Regulatory elements: ✓ Tropomyosin: double helix that lies in the groove between actin filaments. In the resting state shields a specific myosin binding region on the actin filament. ✓ Troponin are actually complexes of three loosely bound protein subunits: Troponin I has a strong affinity for actin. Troponin T for tropomyosin. Troponin C for calcium ions. Troponin T is tightly bound to tropomyosin forming troponin-tropomyosin complex. This complex covers the binding sites for myosin heads on the actin filament, so contraction is inhibited. Fig. 2 (A) Cross-bridge between myosin and actin filaments in the resting state. (B) Ca++ binds to troponin C and this results in a rearrangement of the troponin complex, followed by movement of the tropomyosin filament and exposure of the myosin binding site on actin. Excitation-contraction coupling mechanism It is the process by which an action potential initiates the muscle contraction. This is achieved by converting a chemical signal into a mechanical energy via the action of contractile proteins. The crucial event is the increase in intracellular calcium. It involves the following steps: 1. Stimulation of myelinated motor nerve supplying a skeletal muscle leading to generation of action potential, which spreads along both sides of the sarcolemmal membrane. 2. The action potential spreads to the depth of the myofibrils via the T-tubular system (extending from the sarcolemmal membrane). 3. Release of calcium ions from the lateral sacs of the sarcoplasmic reticulum and its diffusion to the thick and thin filaments. 4. Binding of Ca++ to troponin C, uncover the binding sites of myosin on the actin filaments. This is due to inhibition of troponin-tropomyosin complex and lateral movement of tropomyosin. ATP is splitted to supply the energy needed for muscular contraction. 2 Dr. Seham Zakaria 5. Sliding of the thin filaments over the thick filaments, due to the formation of cross linkages between myosin and actin, leading to muscular contraction. 6. More and more shortening is obtained by disconnection ,cocking ( return to right angle), reconnection and, swiveling of myosin heads to the binding sites on actin filaments. 7. Active reuptake of calcium by the sarcoplasmic reticulum to be stored for the next action potential. The energy needed is obtained from the break down of ATP, so ATP is used in muscular contraction and relaxation. 8. Once the calcium is reuptaken by the sarcoplasmic reticulum, the interaction between myosin and actin stops and muscular relaxation occurs. Calcium induced Calcium release (CICR): An increase in intracellular [Ca++] causes contraction of the myocardial cell by a sliding filament. Opposite each Z line there is a tubular structure, the T tubule, running at right angles to the plasma membrane of the cell. The T tubules help to spread electrical excitation rapidly into the cell and they run close to the sarcoplasmic reticulum (SR) in which Ca++ ions are stored. The Ca++ used to trigger contraction of cardiac muscle therefore comes from two sources, the SR (about 75% of the total) and also transmembrane flux of Ca ++ from the extracellular fluid (about 25% of the total). This is in contrast to skeletal muscle which only uses SR stores of Ca++ for contraction. Interesting facts: Contraction of all three types of muscle, skeletal, cardiac and smooth muscle is triggered by a rise in intracellular [Ca ++]. The source of Ca++ for the contractile mechanism is different in the three muscle types. When an action potential occurs in a cardiac muscle cell it triggers an initial increase in the intracellular calcium ion [Ca++i] concentration. The action potential results in an inward flow of calcium from the extracellular fluid. This takes place through L-type calcium channels located in the T tubules and in the plasma membrane. The initial small increase in [Ca++i] causes the release of further calcium ions from the SR stores—the so-called calcium-induced calcium release. This is mediated by a Ca++ binding site on the SR which is part of a calcium channel protein often referred to as a ‘ryanodine-sensitive receptor’. As a result of calcium release from the SR the [Ca++i] increases, normally to about 0.5–2μmol/L. In heart failure there are significant alterations in how myocyte [Ca ++] is regulated. During relaxation some Ca++ has to be exported back out of the cell and some replaced into the SR. 1. Ca++ is predominantly expelled from the myocyte via a 3Na + / Ca++ exchanger which uses the inward ‘downhill’ movement of the 3Na + to move Ca++ out of the 3 Dr. Seham Zakaria cell. This mechanism per se does not consume ATP although the Na +/K+-ATPase actively expels Na+ across the plasma membrane in order to maintain the electrochemical gradient for Na+. 2. A portion of the Ca++ is actively expelled from the cell across the plasma membrane by Ca++ATPases. 3. Ca++ATP is also used to pump Ca++ back into the SR stores. Within the SR much of the calcium is stored as ionized Ca ++. However some is attached to calcium binding proteins of which calsequestrin is one of the most important. Fig. 3 Regulation of intracellular [Ca++] in cardiac muscle. Relation between electrical and mechanical responses of the cardiac muscle. The relationship between the cardiac action potential (electrical) and cardiac contraction (mechanical) is shown in Figure 48 The whole contraction and part of the relaxation in which the heart is refractory (can not be stimulated) coincide with phases 0, 1, 2 and part of phase 3. During these phases the heart is in Absolute Refractory Period (ARP). The long action potential duration with its long ARP ensures that tetanus cannot be induced in the heart 4 Dr. Seham Zakaria Fig.48: Relation between electrical and mechanical responses of the cardiac muscle There are two types of contraction: Isometric contraction where the fibers contract without shortening. The tension developed in them rises very much and most of the energy is liberated as heat. No work is done. The pressure inside the heart raises to a high level, which is essential to open the aortic and pulmonary valves. The volume of the heart remains constant. Isotonic contraction where the cardiac fibers shorten but the tension developed in them does not increase i.e. it remains the same throughout work. The pres- sure inside the heart raises only slightly, the volume of the heart diminished and the heart pumps its blood into the lungs or the body by decreasing its size. Regulation of force of contraction of cardiac muscle by the autonomic nervoius system As previously noted, the force of cardiac muscle contraction depends on the intracellular [Ca++]. The force of contraction depends also on the number of crossbridges formed, a parameter which in turn depends on the [Ca ++] inside the muscle cell. Under resting conditions only a relatively small proportion of the potential total cross-bridge formation actually occurs. This means that physiological stimulation, via sympathetic nervous system activation, and drugs which increase intracellular [Ca++] can generate a more forceful cardiac muscle contraction than occurs at resting levels. Physiological stimulation of sympathetic nerves to the heart results in an increased force of contraction. The β1-adrenoceptor activation leads to a rise in intracellular cyclic AMP , a second messenger which activates several protein kinases. Subsequent phosphorylation of the protein phospholamban accelerates transport of Ca++ into the SR thus favouring retention of Ca++ in the SR at the expense of efflux back across the plasma membrane. Contractility of the heart is therefore increased by raising the amount of Ca++ stored in the SR. The rate of relaxation of cardiac muscle is also increased as the Ca++ re-enters the SR more quickly. The effects of cAMP in 5 Dr. Seham Zakaria these events can be manipulated by drugs such as milrinone and caffeine which act as phosphodiesterase inhibitors and hence prolong the half-life of cAMP. Also sympathetic stimulation causes Phosphorylation of L-type calcium channels will increase their permeability to calcium allowing entry of more calcium to cardio-myocyte Positive inotropes Are agents which increase contractility sympathetic stimulation Sympathomimetic agent Negative inotropes Are agents which decrease contractility Intracellular acidosis (high H+) Reduced binding of Ca++ to troponin and a decrease in the force developed by the crossbridges that do form. Calcium-channel-blocking drugs REFERENCES: Human Physiology - From Cells to Systems 7th ed – Chapter 9 New Guyton 14th edition.pdf-Chapter 9 The cardiovascular system, 2ed edition, Noble A etal, Page 18-20, part of page 49,50 6