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European Heart Journal 1991 12(Supplement F):88-98; doi:10.1093/eurheartj/12.suppl_F.88
Copyright © 1991 by the European Society of Cardiology.
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© 1991 The European Society of Cardiology

Alpha1adrenergic system and arrhythmias in ischaemic heart disease

T. Kurz, K. A. Yamada, S. D. DaTorre and P. B. Corr

Cardiovascular Division, Department of Internal Medicine and Department of Molecular Biology and Pharmacology, Washington University School of Medicine St Louis, Missouri, USA

Correspondence: Professor Peter B. Corr, Washington University School of Medicine, Cardiovascular Division, Box 8086, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.

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+ A TPase 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}1-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 β-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 β-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 norepi-nephrine. 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.

Key Words: Adrenergic receptors • hypoxia • inositol phosphates • acylcarnitines • catecholamines


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