Normalization of the calcineurin pathway underlies the regression of hypertensive hypertrophy induced by NHE-1 inhibition.

ENNIS IL; GARCIARENA CD; ESCUDERO EM; PEREZ NG; DULCE RA; CAMILIÓN DE HURTADO MC; CINGOLANI HE

CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY (ONLINE)

NRC Research Press

Lugar: Ottawa, Canadá; Año: 2007 vol. 85 p. 301 - 310

1205-7541

NHE-1-inhibition induces cardiac hypertrophy regression/prevention in several experimental models although the intracellular events involved remain unclarified. We aimed to determine whether calcineurin/NFAT pathway mediates this effect of NHE-1 inhibitors. Spontaneously hypertensive rats (SHR) with cardiac hypertrophy were treated with the NHE-1 inhibitors cariporide and BIIB723 during 30 days. Wistar rats served as normotensive controls. Hearts were studied by echocardiography, immunoblotting and real-time RT-PCR. Cytoplasmic Ca2+ and calcineurin Ab expression were measured in cultured neonatal rat ventricular myocytes (NRVM) stimulated with endothelin-1 for 24 hrs. NHE-1 blockade induced cardiac hypertrophy regression (heart weight/body weight = 3.63±0.07 vs. 3.06±0.05 and 3.02±0.13 for untreated-; cariporide- and BIIB723-treated SHR, respectively; P<0.05), decreased myocardial BNP, calcineurin Ab and nuclear NFAT expressions. Echocardiographic evaluation demonstrated a reduction in left ventricular wall thickness without changes in cavity dimensions or a significant decrease in blood pressure. NHE-1 inhibitors treatment did not affect myocardial stiffness or endocardial shortening, but increased mid-wall shortening, suggesting that a positive inotropic effect develops after hypertrophy regression. Cariporide normalized the increased diastolic Ca2+ and calcineurin Ab expression observed in ET-1-stimulated NRVM. In conclusion our data suggest that inactivation of calcineurin/NFAT pathway may underlie the regression of cardiac hypertrophy induced by NHE-1 inhibition.