Abstract
The binding of β-adrenergic agonists such as norepinephrine and isoproterenol to the β-1 adrenergic receptor (AR) in the sarcolemma of the ventricular myocyte increases intracellular levels of cAMP via Gs protein-induced stimulation of adenyl cyclase. cAMP activates protein kinase A (PKA), which causes phosphorylation of proteins involved in Ca2+ homeostasis, such as phospholamban and the L-type Ca2+ channel, increasing the intracellular calcium ion concentration ([Ca2+]i) transient, and thus causing a positive inotropic effect. It is now very well established that patients with congestive heart failure due to ischemic or idiopathic dilated cardiomyopathy are in a hyperadrenergic state.1 Treatment of these patients with β-adrenergic receptor-blocking drugs reduces morbidity and mortality,2 improves ventricular function, and reverses pathological remodeling.3 Clinical and experimental animal studies have suggested a number of mechanisms by which chronic exposure to this class of drugs, which have a negative inotropic effect in normal myocardium, could have an apparently paradoxical beneficial effect in failing myocardium. See p 2459 Seminal work by Bristow and associates4 showed that β-1 AR density is reduced in the failing myocardium, and receptor density is increased by treatment with some β-AR blockers.5 An increase in β-receptor density may restore toward normal an available positive inotropic reserve in patients with heart failure. In isolated myocytes, a cytotoxic effect of prolonged adrenergic stimulation can be demonstrated,6 suggesting that β-blockade may reduce a deleterious effect of the chronic hyperadrenergic state on myocyte survival. Treatment with β-blockers also slows the heart rate. Because failing myocardium displays a decrease in contractility with increasing rate of stimulation,7 this may improve ventricular function. At slow rates of stimulation, the myocyte action potential is prolonged, allowing for more Ca2+ influx via Na/Ca exchange, and permitting more complete relaxation and reloading …
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