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MECHANISM OF CONTRACTION
Myocardial cells contract as a result of the interac-tion of two overlapping, rigid contractile proteins, actin and myosin. These proteins are fixed in posi-tion within each cell during both contraction and relaxation. Dystrophin, a large intracellular protein, connects actin to the cell membrane (sarcolemma). Cell shortening occurs when the actin and myo-sin are allowed to fully interact and slide over one another. This interaction is normally prevented by two regulatory proteins, troponin and tropomyosin; troponin is composed of three subunits (troponin I, troponin C, and troponin T). Troponin is attached to actin at regular intervals, whereas tropomyo-sin lies within the center of the actin structure. An increase in intracellular Ca2 concentration (from about 10–7 to 10–5 mol/L) promotes contraction as Ca2 ions bind troponin C. The resulting conforma-tional change in these regulatory proteins exposes the active sites on actin that allow interaction with myosin bridges (points of overlapping). The active site on myosin functions as a magnesium-dependent ATPase whose activity is enhanced by the increase in intracellular Ca2 concentration. A series of attach-ments and disengagements occur as each myosin bridge advances over successive active sites on actin. Adenosine triphosphate (ATP) is consumed dur-ing each attachment. Relaxation occurs as Ca2 is actively pumped back into the sarcoplasmic reticu-lum by a Ca2–Mg2-ATPase; the resulting drop in intracellular Ca2 concentration allows the tropo-nin–tropomyosin complex to again prevent the interaction between actin and myosin.
The quantity of Ca2+ ions required to initiate con-traction exceeds that entering the cell through slow calcium channels during phase 2. The small amount that does enter through slow calcium chan-nels triggers the release of much larger amounts of Ca2+ stored intracellularly (calcium-dependent cal-cium release) within cisterns in the sarcoplasmic reticulum.
The action potential of muscle cells depolarizes their T systems, tubular extensions of the cell mem-brane that transverse the cell in close approximation to the muscle fibrils, via dihydropyridine recep-tors (voltage-gated calcium channels). This initial increase in intracellular Ca2+ triggers an even greater Ca2+ inflow across ryanodine receptors, a nonvoltage-dependent calcium channel in the sarcoplasmic reticulum. The force of contraction is directly depen-dent on the magnitude of the initial Ca 2+ influx. During relaxation, when the slow channels close, amembrane-bound ATPase actively transports Ca2+ back into the sarcoplasmic reticulum. Ca2+ is also extruded extracellularly by an exchange of intracel-lular Ca2+ for extracellular sodium by an ATPase in the cell membrane. Thus, relaxation of the heart also requires ATP.
The quantity of intracellular Ca2+ available, its rate of delivery, and its rate of removal determine, respectively, the maximum tension developed, the rate of contraction, and the rate of relaxation. Sym-pathetic stimulation increases the force of contrac-tion by raising intracellular Ca 2+ concentration via a β1-adrenergic receptor-mediated increase in intra-cellular cyclic adenosine monophosphate (cAMP) through the action of a stimulatory G protein. The increase in cAMP recruits additional open calcium channels. Moreover, adrenergic agonists enhance the rate of relaxation by enhancing Ca 2+ reuptake by the sarcoplasmic reticulum. Phosphodiesterase inhibitors, such as inamrinone, enoximone, and mil-rinone, produce similar effects by preventing the breakdown of intracellular cAMP. Digitalis glyco-sides increase intracellular Ca2+ concentration through inhibition of the membrane-bound Na+– K+-ATPase; the resulting small increase in intracel-lular Na+ allows for a greater influx of Ca2+ via the Na+–Ca2+ exchange mechanism. Glucagon enhances contractility by increasing intracellular cAMP levels via activation of a specific nonadrenergic receptor. The new agent levosimendan is a calcium sensitizer that enhances contractility by binding to troponin C. In contrast, release of acetylcholine following vagal stimulation depresses contractility through increased cyclic guanosine monophosphate (cGMP) levels and inhibition of adenylyl cyclase; these effects are mediated by an inhibitory G protein. Acidosis blocks slow calcium channels and therefore also depresses cardiac contractility by unfavorably alter-ing intracellular Ca 2+ kinetics.
Studies suggest that volatile anesthetics depress cardiac contractility by decreasing the entry of Ca2+ into cells during depolarization (affect-ing T- and L-type calcium channels), altering the kinetics of its release and uptake into the sarcoplas-mic reticulum, and decreasing the sensitivity of con-tractile proteins to Ca2+. Halothane and enflurane seem to depress contractility more than isoflurane, sevoflurane, and desflurane. Anesthetic-inducedcardiac depression is potentiated by hypocalcemia, β-adrenergic blockade, and calcium channel block-ers. Nitrous oxide also produces concentration-dependent decreases in contractility by reducing the availability of intracellular Ca 2+ during contraction. The mechanisms of direct cardiac depression from intravenous anesthetics are not well established, but presumably involve similar actions. Of all the major intravenous induction agents, ketamine seems to have the least direct depressant effect on contrac-tility. Local anesthetic agents also depress cardiac contractility by reducing Ca2+ influx and release in a dose-dependent fashion. The more potent (at nerve block) agents, such as bupivacaine, tetracaine, and ropivacaine, more significantly depress left ventric-ular contractility than less potent (at nerve block) agents, such as lidocaine or chloroprocaine.
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