Alpha 1-adrenergic system and arrhythmias in ischaemic heart disease.

Abstract

Several lines of experimental evidence obtained over the last decade indicate that alterations in the alpha 1-adrenergic receptor system may contribute significantly to arrhythmogenesis in the ischaemic heart. Under normal physiological conditions, alpha 1-adrenergic stimulation of myocytes elicits a modest increase in inotropy, a lengthening of repolarization secondary to a decrease in IK through activation of protein kinase C, and a decrease in automaticity in Purkinje cells due to an increase in Na+/K+ ATPase activity. These findings suggest that alpha 1-adrenergic stimulation of the myocardium would elicit an antiarrhythmic effect. However, during both early ischaemia and reperfusion there is an enhanced responsivity to alpha-adrenergic stimulation and a potent antiarrhythmic effect of alpha 1-adrenergic blockade in several species including the conscious dog. This enhanced alpha-adrenergic responsivity may be due to an increase in alpha 1-adrenergic receptors in ischaemic myocardium originating from a site distinct from the intracellular site for trafficking of beta-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 alpha 1-adrenergic receptors in response to severe hypoxia (PO2 = less than 15 mmHg) associated with marked sarcolemmal accumulation of long-chain acylcarnitines (LCA) secondary to hypoxia-induced inhibition of beta-oxidation of fatty acids. The increase in alpha 1-adrenergic receptors is prevented by inhibition of carnitine acyltransferase I which precludes accumulation of LCA. The sarcolemmal accumulation of LCA increases membrane fluidity, suggesting that the alpha 1-adrenergic receptor may be latent within or near the sarcolemma and becomes accessible to a surface ligand only as membrane fluidity is altered. This conclusion is also supported by our findings that hypoxia elicits a marked increase in the coupling of the alpha 1-adrenergic receptor to inositol 1,4,5-trisphosphate (IP3) production in canine myocytes exposed to norepinephrine. IP3 has been shown to mobilize Ca2+ from the sarcoplasmic reticulum, thereby modulating the levels of intracellular Ca2+. Stimulation of hypoxic myocytes with norepinephrine also results in the appearance of delayed after-depolarizations and triggered rhythms, probably in response to an increase in intracellular Ca2+. In conclusion, these findings indicate that the alpha 1-adrenergic system can contribute to arrhythmogenesis in the ischaemic heart and that approaches to reduce the incidence of sudden cardiac death should include blockade of alpha 1-adrenergic receptors.