Many lines of evidence indicate that adrenomedullin (AM) through its coronary vasodilatory and inotropic effects, exerts a major cardiac protective action. Conversely, endothelins (ETs) exert a cardiac detrimental action, which seems to be mainly mediated by the ETA receptor, whose activation promotes coronary constriction and decreases cardiac blood flow. Hence, we have investigated by immunocytochemistry (ICC) and autoradiography the acute effects of ET-1 on endogenous AM system of adult rat heart. Isolated hearts were perfused for 20 min, according to the Langendorff technique, with 2x10−9 M ET-1__AMB__lsqb;1-21__AMB__rsqb; or ET-1__AMB__lsqb;1-31__AMB__rsqb;, which are mixed ETA/ETB and selective ETA receptor agonists, respectively. ICC demonstrated AM-immunoreactivity (IR) in cardiomyocytes, endocardium and especially in the wall of coronary vessels. Quantitative densitometry showed that ET-1__AMB__lsqb;1-31__AMB__rsqb;, but not ET1__AMB__lsqb;1-21__AMB__rsqb;, significantly decreased AM-IR in coronary vessels, thereby suggesting that ET-1 elicits AM release in the heart through the activation of ETA receptors. Autoradiography demonstrated __AMB__lsqb;125I__AMB__rsqb;AM-binding sites in cardiomyocytes and especially in the wall of coronary venules, and treatment with both ET-1s did not apparently affect them. This location af AM receptors suggests that AM raises cardiac blood flow by evoking coronary artery dilation indirectly, probably via its stimulating effect on NO production, and by decreasing postcapillary resistance via cardiac vein dilation. Collectively, our findings indicate that important functional interrelationships occur between ET and AM systems in the rat heart, where ETs may at least partly hamper their own ETA receptor-mediated decrease in blood flow by increasing the local release of endogenous AM.

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