Principles of excitation-contraction coupling in the cardiac myocyte. Calcium enters the myocyte through L-type calcium channels that are modulated by a- and p-adrenergic receptors. This small quantity of calcium triggers release of the large reservoir of intracellular calcium stored in the SR by activation of the SR calcium release channel (ryanodine receptor). Calcium is resequestered in the SR by the SR calcium-ATPase. Calcium is extruded from the cell largely through the Na+-Ca++ exchanger and the sarcolemmal calcium ATPase. p-Adrenergic agonists (e.g., dobutamine) bind to the p-adrenoceptor and activate a stimulatory G protein to couple with adenylyl cyclase to convert ATP to cAMP Phosphodiesterase inhibitors (e.g., milrinone) increase intracellular cAMP levels by blocking the degradation of cAMP by phosphodiesterases. p-Adrenergic antagonists (e.g., metoprolol, carvedilol) bind to the same site and prevent endogenous catecholamines (e.g., norepinephrine) from binding to that site and activating a stimulatory G protein. a-Adrenergic antagonists (e.g., prazosin) and angiotensin II receptor blockers (e.g., valsartan, losartan) similarly prevent the endogenous mediators (i.e., norepinephrine, angiotensin II, respectively) from increasing intracellular ionized free calcium levels in the cardiac myocyte. ACE inhibitors (e.g., captopril, fosinopril, lisinopril) block conversion of inert angiotensin I to active angiotensin II by ACE. Digitalis glycosides initially increase intracellular Na+ levels by binding to the Na+-K+ ATPase. The increase in intracellular Na+ causes the Na+-Ca++ exchanger to extrude Na+ from the myocyte in exchange for extracellular Ca++. This increases intracellular ionized free calcium levels sufficiently to enhance contractility.
toxicity, the lack of understanding of its mode of action, and the lack of any definitive evidence describing its safety and efficacy.
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