Apelin, the novel agonist of the APJ receptor, increases inotropism by endogenous release of endothelin.

PÉREZ NG; AIELLO EA; CINGOLANI HE

Chicago, Illinois, USA

Conferencia; 58th Annual Fall Conference and Scientific Sessions of the Council for High Blood Pressure Research in association with the Council on the Kidney in Cardiovascular Disease.; 2004

G protein coupled receptors (GPCRs) are the major group of transmembrane proteins responsible for signal transduction to cytosol. Only half of the ~300 described GPCRs are activated by known agonists while those for the other half remain unknown, reason by which these receptors are called “orphan”. An agonist for one of these receptors, the APJ, with a structural similarity to the angiotensin II AT1 receptor, was recently described and called Apelin (A). mRNA of A was found in several tissues including the myocardium, where it has a potent positive inotropic action. The objective of this study was to examine the possibility that A, similarly to Angiotensin II, could act by promoting the release of one of the endothelin (ET) isoforms, which in turn, and through the ETA receptors, would increase cardiac inotropism. Cat papillary muscles isometrically contracting (0.2 Hz) and isolated unloaded myocytes were used. Developed force (DF) after 50 pmol/L A in the presence and absence of ETA receptors blockade (300 nmol/L BQ123) was measured in papillary muscles and shortening after 5 to 500 pmol/L A in single cells. 50 pmol/L A increased DF by 23 ± 2 % (n=4), effect that was prevented by BQ123 (-4 ± 3 %, n=4), suggesting that endogenous release of one of the ET isoforms mediates the effect. Parallel experiments demonstrated that BQ123 cancels the positive inotropic effect of ET-2 and ET-3 but not that of ET-1. Since in multicellular preparations the source of ET could be the myocyte itself (autocrine) or non-myocyte cells (paracrine), we performed experiments in isolated myocytes. A lacked of effect on basal contractility, being the percent shortening 9 ± 1 % and 10 ± 1 % (n=8) before and after 15 min of 50 pmol/L A respectively. In conclusion, although higher doses of A may increase force by other mechanisms, a dose as low as 50 pmol/L A produces a force increase of ~20% entirely due to release of endogenous ET by cells other than myocytes. Since BQ123 abolished the effect of A but did not prevent the inotropic effect of ET-1, we may conclude that ET-1 seems not to be the isoform released by A. Thus, ET-2 or ET-3 may bind to the myocyte ETA receptors initiating the characteristic intracellular signaling pathway by which ETs promote the positive inotropic effect