turopean Heart Journal (1W1) 12 [Supplement F), 88-98 Alpharadrenergic system and arrhythmias in ischaemic heart disease

Several lines of experimental evidence obtained over the last decade indicate that alterations in the a,-adrenergic receptor system may contribute significantly to arrhythmogenesis in the ischaemic heart. Under normal physiological conditions, a,-adrenergic stimulation of myocytes elicits a modest increase in inotropy, a lengthening of repolarization secondary to a decrease in lK through activation of protein kinase C, and a decrease in automaticity in Purkinje cells due to an increase in Na +/K+ A TPase activity. These findings suggest that a,-adrenergic stimulation of the myocardium would elicit an antiarrhythmic effect. However, during both early ischaemia and reperfusion there is an enhanced responsivity to a-adrenergic stimulation and a potent antiarrhythmic effect of a,-adrenergic blockade in several species including the conscious dog. This enhanced a-adrenergic responsivity may be due to an increase in a,-adrenergic receptors in ischaemic myocardium originating from a site distinct from the intracellular site for trafficking of ^-adrenergic receptors, possibly within or near the sarcolemma. Recently, we developed an isolated adult canine ventricular myocyte preparation which also exhibits a 2- to 3-fold reversible increase in a,-adrenergic receptors in response to severe hypoxia (PO2 = <15mmHg) associated with marked sarcolemmal accumulation of long-chain acylcarnitines (LCA) secondary to hypoxia-induced inhibition of ^-oxidation of fatty acids. The increase in a,-adrenergic receptors is prevented by inhibition of camitine acyltransferase I which precludes accumulation of LCA. The sarcolemma