Influence of the Na+/H+ exchanger activation by the autocrine loop angiotensinII/Endothelin upon the Na+/Ca2+ exchanger in the heart

VILLA-ABRILLE MC, DULCE RA, PÉREZ NG, CAMILIÓN DE HURTADO MC, AIELLO EA, CINGOLANI HE

San Antonio, Texas, EEUU

Congreso; XV Scientific Meeting of the Interamerican Society of Hypertension; 2003

Interamerican Society of Hypertension

We recently showed that Angiotensin II (Ang II) stimulates the cardiac Na+/Ca2+ exchanger (NCX) activity in cat ventricular myocytes by the autocrine action of endogenously released Endothelin (ET). In experiments performed in isometrically contracting cat papillary muscles an inotropic response to a low dose of Ang II (1 nM) of 23.4±2.1 % (n=4) was detected. This positive inotropic effect of Ang II was abolished by the blocker of the Na+/H+ exchanger (NHE), cariporide, by the antagonist of the ET receptors, TAK044 and by the inhibitor of the NCX reverse mode, KB-R7943. The same dose of Ang II induced an increase in intracellular Na+ (Na+i) (fluorescence of SBFI) of 2.2±0.1 mM (without changes in pHi) that was suppressed by TAK044 and cariporide. Similar increases in force (21.4±1.1 %, n=4) and Na+i (2.4±0.4 mM, n=4) were induced by 5 nM ET-1 and were also suppressed by TAK044 and cariporide. The increase in force but not in Na+i was abolished by KB-R7943. These data suggest that the inotropic response to a low dose of Ang II is mediated by release of endogenous ET and support the hypothesis that the Ang II/ET-induced increase in Na+i by activation of the NHE can produce a negative shift in the reversal potential of the NCX (ENCX), increasing the time for the NCX working in reverse mode during the action potential and promoting cell Ca2+ influx. In order to analyze this hypothesis, we evaluated the effects of ET-1 on ENCX (whole-cell) in isolated cat ventricular myocytes. ET-1 produced a negative shift in ENCX (ΔENCX: ET-1 1 nM= -8±2 mV, ET-1 10 nM= -15±3 mV, n=6). This shift was prevented by cariporide (ΔENCX: ET-1 1 nM= -0.5±3 mV, ET-1 10 nM= +2.1±3 mV, n=5) indicating that it was produced by the increase in Na+i induced by stimulation of the NHE by ET-1. The ET-1-induced increase in Na+i estimated from the ENCX negative shift was 2.3±0.8 mM and 4.4±0.9 mM for ET-1 1 nM and 10 nM, respectively (n=6). The results of this study suggest that Ang II at low doses induces the release of ET from the myocyte. This peptide in an autocrine fashion induces the activation of the NHE, increases Na+i and changes ENCX, promoting Ca2+ influx that leads to a positive inotropic effect.