CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Involvement of increased intracellular sodium level in endothelin-1-induced hypertrophy
DULCE RA; GARCIARENA CD; ENNIS IL; CALDIZ C; CORREA MV; CHIAPPE DE CINGOLANI GE; CAMILIÓN DE HURTADO MC
Congreso; Tenth International Conference on Endothelin; 2007
Elevation of intracellular sodium concentration ([Na+]i) has been documented in hypertrophied failing myocardium. The prohypertrophic peptide endothelin-1 (ET-1) stimulates Na+/H+ exchange (NHE), which constitutes an important Na+ influx pathway. The aim of this work was to explore whether NHE-mediated increases in [Na+]i participates in the hypertrophic effect of ET-1 in cultured neonatal rat ventricular myocytes (NRVM). ET-1-treated (5 nmol/L) NRVM showed, in comparison with control NRVM, a) increased NHE activity (proton extrusion 13.7 ± 2.8 vs. 2.5 ± 1.2 mmol/L/min, n=5, P<0.05) with normal exchanger protein expression; b) higher [Na+]i (8.1 ± 1.2 vs. 4.2 ± 1.3 mmol/L, n=4, P<0.05) and total cell [Ca2+]i (636 ± 117 vs. 346 ± 85 nmol/L, n=9 vs. 11 respectively, P<0.05); c) larger cell surface area and 3H-phenylalanine incorporation (131 ± 3 and 220 ± 12 % of control, respectively, P<0.05). These effects were cancelled by NHE inhibition with 1 umol/L cariporide. Elevated [Na+]i may reduce Ca2+ efflux through Na/Ca exchange (NCX) or promote the reverse NCX mode, thereby increasing cell Ca2+. ET-1 treatment did not modify the relaxation of caffeine-induced Ca2+ transients (Tau 4.6 ± 1.3 and 3.5 ± 0.8 sec, n=5 in control and ET-1-treated NRVMs, respectively) rejecting the former possibility. Reverse NCX mode was inhibited either with 5 umol/L KB R7943 or raising extracellular [Na+] from 137 to 237 mmol/L to compensate for the rise in [Na+]i and keep driving force for NCX similar to that of control conditions. With KB R7943, total cytosolic Ca2+ was reduced to 326 ± 27 nmol/L in ET-1-treated NRVM (n=12, NS compared to controls). In addition, both ways of inhibition of reverse NCX mode prevented the hypertrophic effect of ET-1 in NRVM. The results show the involvement of NHE-mediated Na+ influx and the secondary stimulation of reverse NCX mode in the ET-1 hypertrophic effect in NRVM. In addition, they give support to propose the inhibition of reverse NCX mode, as it was for NHE inhibition, to be a potential preventive/therapeutic strategy for cardiac hypertrophy.