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Dual role of endothelin-1 via ET_A and ET_B receptors in regulation of cardiac contractile function in mice

¹Department of Pharmacology and Toxicology,²Biocenter Oulu, and³Department of Pathology, University of Oulu, 90014 Oulu, Finland; and⁴Heart Institute, Faculty of Medicine, University of Pécs, 7624 Pécs, Hungary

Submitted 7 June 2002 ; accepted in final form 19 February 2003

An increase in coronary perfusion pressure leads to increased cardiac contractility, a phenomenon known as the Gregg effect. Exogenous endothelin (ET)-1 exerts a positive inotropic effect; however, the role of endogenous ET-1 in the contractile response to elevated load is unknown. We characterized here the role of ET_A and ET_B receptors in regulation of contractility in isolated, perfused mouse hearts subjected to increased coronary flow. Elevation of coronary flow from 2 to 5 ml/min resulted in 80 ± 10% increase in contractile force (P < 0.001). BQ-788 (ET_B receptor antagonist) augmented the load-induced contractile response by 35% (P < 0.05), whereas bosentan (ET_A/B receptor antagonist) and BQ-123 (ET_A receptor antagonist) attenuated it by 34% and 56%, respectively (P < 0.05). CV-11974 (ANG II type 1 receptor antagonist) did not modify the increase in contractility. These results show that endogenous ET-1 is a key mediator of the Gregg effect in mouse hearts. Moreover, ET-1 has a dual role in the regulation of cardiac contractility: ET_A receptor-mediated increase in contractile force is suppressed by ET_B receptors.

angiotensin II; coronary pressure; Gregg effect

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