STIMULATION OF THE REVERSE MODE OF THE Na+/Ca2+ EXCHANGER BY ENDOTHELIN-1 AND ITS INFLUENCE ON CARDIAC CONTRACTILITY.

AIELLO EA; VILLA-ABRILLE MC; DULCE RA; PÉREZ NG

Iguazú, Argentina

Congreso; Satellite Meeting to the XVIII World Congress of the International Society for Heart Research (ISHR), XIII Meeting of the International Society for Heart Research (ISHR), Latin American Section.; 2004

  The present work was directed to study which are the signaling pathways involved in the positive inotropic effect (PIE) of endothelin-1 (ET-1). Cat papillary muscles were used for developed force (DF) and intracellular Na+ concentration ([Na+]i) measurements and isolated cat ventricular myocytes for patch-clamp experiments. ET-1 (5 nM) induced a PIE and an associated increase in [Na+]i that were completely prevented by the Na+/H+ exchanger (NHE) inhibitor, HOE642 (1 mM). The blocker of the reverse mode of the Na+/Ca2+ exchanger (NCX), KB-R7943 (5 mM) totally reversed the ET-1-induced PIE. Partial inhibition of the Na+/K+ pump through reduction of the extracellular K+ concentration ([K+]o) promoted a similar KB-R7943-sensitive PIE to that produced by ET-1. However, low [K+]o induced a greater increase in [Na+]i than that observed with ET-1. The ratio DDF to D[Na+]i were 10.1±1.2 (n=5) with ET-1 and 5.9±1.1 (n=4, P<0.05) with low [K+]o. In isolated myocytes, ET-1 (10 nM) increased the NCX current (INCX) and negatively shifted the reversal potential of the NCX (ENCX) (DENCX=-13.8±4.8 mV, n=8). The ENCX shift was totally prevented by HOE642 (DENCX=-0.1±3.9 mV, n=9). In the presence of this blocker the increase in INCX outward (reverse mode) induced by ET-1 was significantly lower (at 0 mV, 1.74±0.38 fold, n=9) than that in the absence of the NHE inhibitor (3.57±0.79 fold, n=8, P<0.05), suggesting that ET-1 increases INCX outward indirectly, by the increase in driving force due to the ENCX negative shift and directly, stimulating the NCX per se. Taking together, the results indicate that whereas the ET-1-induced increase in [Na+]i produced by the activation of the NHE seems to be a mandatory pathway to drive the NCX in reverse mode and enhance contractility, a direct stimulation of the NCX appears to additionally contribute to the PIE of this peptide.