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Control of Normal Cardiac Contractility
The vigor of contraction of heart muscle is determined by several processes that lead to the movement of actin and myosin filaments in the cardiac sarcomere (Figure 13–1). Ultimately, contraction results from the interaction of activator calcium (during systole) with the actin-troponin-tropomyosin system, thereby releasing the actin-myosin interaction. This activator calcium is released from the sarcoplasmic reticulum (SR). The amount released depends on the amount stored in the SR and on the amount of trigger calcium that enters the cell during the plateau of the action potential.
The determinants of calcium sensitivity, ie, the curve relating the shortening of cardiac myofibrils to the cytoplasmic calcium con-centration, are incompletely understood, but several types of drugs can be shown to affect calcium sensitivity in vitro. Levosimendan is the most recent example of a drug that increases calcium sensi-tivity (it may also inhibit phosphodiesterase) and reduces symp-toms in models of heart failure.
A recent report suggests that an experimental drug, omecantivmecarbil (CK-1827452), alters the rate of transition of myosinfrom a low-actin-binding state to a strongly actin-bound force-generating state. Preliminary studies in experimental animal mod-els of heart failure indicate that this agent may provide a new approach to the treatment of heart failure in humans. Clinical tri-als are underway.
A small rise in free cytoplasmic calcium, brought about by calcium influx during the action potential, triggers the opening of calcium-gated, ryanodine-sensitive calcium channels (RyR2) in the mem-brane of the cardiac SR and the rapid release of a large amount of the ion into the cytoplasm in the vicinity of the actin-troponin-tropomyosin complex. The amount released is proportional to the amount stored in the SR and the amount of trigger calcium thatenters the cell through the cell membrane. (Ryanodine is a potent negative inotropic plant alkaloid that interferes with the release of calcium through cardiac SR channels.)
The SR membrane contains a very efficient calcium uptake trans-porter known as the sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA). This pump maintains free cytoplasmic calcium at very low levels during diastole by pumping calcium into the SR. SERCA is normally inhibited by phospholamban; phosphoryla-tion of phospholamban by protein kinase A (eg, by β agonists) removes this inhibition. The amount of calcium sequestered in the SR is thus determined, in part, by the amount accessible to this transporter and the activity of the sympathetic nervous system. This in turn is dependent on the balance of calcium influx (pri-marily through the voltage-gated membrane L-type calcium chan-nels) and calcium efflux, the amount removed from the cell (primarily via the sodium-calcium exchanger, a transporter in the cell membrane). The amount of Ca2+ released from the SR depends on the response of the RyR channels to trigger Ca2+.
The amount of trigger calcium that enters the cell depends on the availability of membrane calcium channels and the duration of their opening. As described, sympathomimet-ics cause an increase in calcium influx through an action on these channels. Conversely, the calcium channel blockers reduce this influx and depress contractility.
This antiporter (NCX) uses the sodium gradient to move calcium against its concentration gradient from the cytoplasm to the extra-cellular space. Extracellular concentrations of these ions are much less labile than intracellular concentrations under physiologic con-ditions. The sodium-calcium exchanger’s ability to carry out this transport is thus strongly dependent on the intracellular concen-trations of both ions, especially sodium.
Na+/K+-ATPase, by removing intracellular sodium, is the major determinant of sodium concentration in the cell. The sodium influx through voltage-gated channels, which occurs as a normal part of almost all cardiac action potentials, is another determinant, although the amount of sodium that enters with each action potential is much less than 1% of the total intracellular sodium. Na+/K+-ATPase appears to be the primary target of digoxin and other cardiac glycosides.
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