Mechanisms contributing to the arrhythmogenic influences of alpha 1-adrenergic stimulation in the ischemic heart.

The majority of deaths associated with ischemic heart disease occur suddenly because of disturbances in cardiac rhythm culminating in ventricular fibrillation. Past research has focused on elucidating the biochemical membrane mechanisms responsible for the adverse electrophysiologic alterations in the ischemic heart, with major emphasis on the influence of adrenergic neural factors. It has been demonstrated that both alpha 1-and beta-adrenergic mechanisms contribute to arrhythmogenesis in the ischemic heart. In the normal heart, alpha 1-adrenergic input has very little effect on electrophysiologic indices. However, during early ischemia and reperfusion, enhanced alpha 1-adrenergic responsivity associated with a twofold reversible increase in alpha 1-adrenergic receptors in vivo has been demonstrated. Likewise, in a variety of species, alpha 1-adrenergic inhibition with prazosin markedly decreases the incidence of malignant ventricular arrhythmias associated with either myocardial ischemia or subsequent reperfusion. One major manifestation of alpha 1-adrenergic receptor activation during reperfusion of ischemic myocardium is an increase in intracellular calcium ion (Ca2+). It has been demonstrated that reperfusion of ischemic myocardium increases intracellular Ca2+ in reversibly injured tissue, and that the gain in intracellular Ca2+ is prevented by alpha 1-adrenergic inhibition with hydroxyphenylethyl aminomethyl tetralone, even when administered just prior to reperfusion. Subsequently, it was demonstrated that the alpha 1-adrenergic-induced increase in mitochondrial Ca2+ contributes to the decline in mitochondrial function. These findings suggest that even single-dose intervention with alpha 1-adrenergic inhibitors may improve markedly the functional recovery and extent of ultimate necrosis in humans after coronary thrombolysis. To investigate the mechanisms responsible for the increase in alpha 1-adrenergic receptors during ischemia, we used isolated adult canine ventricular myocytes exposed to hypoxia. Thirty minutes of hypoxia at 25 degrees C or 10 minutes of hypoxia at 37 degrees C resulted in a threefold reversible increase in the density of surface alpha 1-adrenergic receptors and a threefold increase in the cellular content of long-chain acylcarnitines. Inhibition of carnitine acyltransferase I abolished not only the accumulation of long-chain acylcarnitines during hypoxia but also the increase in alpha 1-adrenergic receptors. Exposure of normoxic myocytes to exogenous long-chain acylcarnitines (1 mumol/liter) for 10 minutes also increased alpha 1-adrenergic receptor number. These findings indicate that the sarcolemmal accumulation of long-cha