Alpha-adrenergic vasoconstriction in the coronary circulation is mediated through alpha-adrenoceptors on cardiac myocytes and subsequent release of endothelin, a very potent, long-lasting vasoconstrictor. Recent studies found that adult cardiac myocytes do not express the preproendothelin gene. Thus we hypothesized that alpha-adrenoceptor stimulation on the cardiac myocytes results in the production of an endothelin-releasing factor, which stimulates the coronary vasculature to produce endothelin. We tested this hypothesis by using an in vitro model in which isolated adult rat cardiac myocytes can be stimulated with an alpha-adrenoceptor agonist (phenylephrine). Their bathing fluid is then transferred to isolated coronary arterioles, and vasoactive responses are measured. To identify the source of endothelin, the endothelin-converting enzyme inhibitor phosphoramidon was added to either the myocytes or the isolated arterioles. Phenylephrine enhanced the vasoconstrictor properties of the myocyte bathing fluid. Administration of phosphoramidon (in either the presence or the absence of phenylephrine) to the myocytes had no effect on the vasoactive properties of the bathing fluid. In contrast, administration of phosphoramidon to the isolated arteriole before administration of the bathing fluid converted vasoconstriction to vasodilation, similar to the effect of the endothelin A receptor antagonist JKC-301, indicating that the endothelin is indeed produced by the coronary vasculature. Administration of the angiotensin type 1 receptor antagonist losartan to the vessel bath enhanced vasodilation to the bathing fluid of the phenylephrine-treated but not control myocytes. In conclusion, during alpha-adrenergic activation cardiac myocytes release a factor, probably angiotensin II, that stimulates the vascular production of endothelin. Although the physiological implications of this mechanism are not obvious, this may represent a protective mechanism that integrates neuronal vasoconstrictor mechanisms with myocardial metabolism, which minimizes periods of both coronary underperfusion and overperfusion.

Adrenergic alpha-Agonists/pharmacology, Animals, Arterioles/physiology, Coronary Circulation/*physiology, Coronary Vessels/*physiology, Endothelin-1/*metabolism, Male, Microcirculation/physiology, Myocytes, Cardiac/drug effects/*metabolism, Phenylephrine/pharmacology, Rats, Rats, Wistar, Vasoconstriction/*physiology
dx.doi.org/10.1152/ajpheart.00522.2003, hdl.handle.net/1765/13631
American Journal of Physiology - Heart and Circulatory Physiology
Erasmus MC: University Medical Center Rotterdam

Merkus, D, Brzezinska, A.K, Zhang, C, Saito, S, & Chilian, W.M. (2005). Cardiac myocytes control release of endothelin-1 in coronary vasculature. American Journal of Physiology - Heart and Circulatory Physiology, 288(5 57-5), 2088–2092. doi:10.1152/ajpheart.00522.2003