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1 Department of Pharmacology and Toxicology, University of Oulu, Biocenter Oulu, Oulu, Finland
2 Department of Pathology, University of Oulu, Oulu, Finland
3 Department of Pharmacology and Toxicology, University of Oulu, Biocenter Oulu, Oulu, Finland; Heart Institute, Faculty of Medicine, University of Pecs, Pecs, Hungary
* To whom correspondence should be addressed. E-mail: heikki.ruskoaho{at}oulu.fi.
Piuhola, Jarkko, Markus Mäkinen, István Szokodi, and Heikki Ruskoaho. Dual Role of Endothelin-1 via ETA and ETB Receptors in Regulation of Cardiac Contractile Function in Mice. — An increase in coronary perfusion pressure leads to increased cardiac contractility, a phenomenon known as the Gregg effect. Exogenous endothelin-1 (ET-1) exerts positive inotropic effect, however, the role of endogenous ET-1 in the contractile response to elevated load is unknown. We characterize herein the role of ETA and ETB receptors in regulation of contractility in isolated, perfused mice 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 (ETB receptor antagonist) augmented the load-induced contractile response by 35% (P<0.05), whereas bosentan (ETA/B receptor antagonist) and BQ-123 (ETA receptor antagonist) attenuated it by 34% and 56%, respectively (P<0.05). CV-11974 (angiotensin 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 mice hearts. Moreover, ET-1 has a dual role in the regulation of cardiac contractility: ETA receptormediated increase in contractile force is suppressed by ETB receptors.
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