A low dose of angiotensin II increases inotropism through activation of reverse Na+/Ca2+ exchange by endothelin release

Objective: This work was aimed to prove that release/formation of endogenous endothelin acting in an autocrine/paracrine fashion contributes to the increase in contractility promoted by a low dose of angiotensin II. Methods: Isolated cat papillary muscles were used for force, pHi, [Na+]i and [Ca2+]i measurements and isolated cat myocytes for patch-clamp experiments. Results: In papillary muscles, 1.0 nmol/l angiotensin II increased force by 23±2% (n=4, P+]i by 2.2±0.2 mmol/l (n=4, P2+ from 0.674±0.11 to 0.768±0.13 μmol/l (n=4, P+]i increase were abolished by inhibition of the Na+/H+ exchanger (NHE) with the inhibitor HOE642, blockade of endothelin receptors with the nonselective antagonist TAK044 and by inhibition of the endothelin-converting enzyme with phosphoramidon. Force but not [Na+]i increase was abolished by inhibition of reverse Na+/Ca2+ exchange (NCX) with the inhibitor KB-R7943. Similar increase in force (21±2%, n=4, P+]i (2.4±0.4 mmol/l, n=4, P+]i. In isolated myocytes, exogenous endothelin-1 dose-dependently increased the NCX current and shifted the NCX reversal potential (ENCX) to a more negative value (ΔENCX: -10±3 and -17±5 mV, with 1 and 10 nmol/l endothelin-1, respectively, n=12). The latter effect was prevented by HOE642. Conclusion: Taken together, the results indicate that a low dose of angiotensin II induces release of endothelin, which, in autocrine/paracrine fashion activates the Na+/H+ exchanger, increases [Na+]i and changes ENCX, promoting the influx of Ca2+ that leads to a positive inotropic effect (PIE).Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare