Cardiac hypertrophy regression by NHE-1 inhibition involved a decrease in diastolic Ca2+ levels and inactivation of the calcineurin/NFAT prohypertrophic pathway.

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

, Colby-Sawyer College, New London, NH. EE.UU

Congreso; Gordon research Conference on Cardiac Regulatory Mechanisms; 2006

Na+/H+ exchanger (NHE-1) inhibition emerges as an antihypertrophic loading-independent pharmacologic intervention. The mechanism involved is not clear and there is no report considering a possible link with the calcineurin (Cn) pathway. SHR with cardiac hypertrophy (CH) were chronically treated with the NHE-1 inhibitors cariporide or BIIB723. Age match untreated SHR were used as controls. No changes in arterial pressure were induced by the NHE-1 inhibitors. After 30 days of treatment rats were sacrifice and hearts weighted and frozen for later examination. NHE-1 blockade induced CH regression (heart weight/body weight was 3.63¡Ó0.07; 3.06¡Ó0.05 and 3.02¡Ó0.13 for untreated, cariporide- and BIIB723-treated SHR; p<0.05, ANOVA) and decreased myocardial BNP expression. Cardiac pump function was investigated by echocardiography at the beginning and end of treatment. Echocardiographic evaluation after completing treatment demonstrated a reduction in left ventricular wall thickness without changes in cavity dimensions or a significant decrease in blood pressure. Treating SHR with the NHE-1 inhibitors did not affect endocardial shortening, but increased mid-wall shortening, suggesting that a positive inotropic effect develops after hypertrophy regression. Calcineurin activity was investigated by quantifying calcineurin Ab expression and NFAT nuclear abundance (the isoform upregulated in CH). Both calcineurin Ab expression and NFAT nuclear abundance were up-regulated in the hypertrophied myocardium of the SHR and the NHE-1 inhibitors normalized these parameters. Since calcineurin requires Ca2+ elevations for its activation we studied in neonatal rat ventricular myocytes (NRVM) the effect of a hypertrophic agonist (endothelin 1) and NHE-1 inhibition on intracellular Na+, Ca2+ and calcineurin Ab expression. Endothelin 1 induced an increase in intracellular Na+ and diastolic Ca2+ levels that were accompanied by up-regulation of calcineurin Ab expression. NHE-1 blockade blunt the increases in Na+ and Ca2+ and normalized calcineurin Ab expression. In conclusion, we demonstrated that the regression of CH by different pharmacologic NHE-1 inhibitors is accompanied by decreased calcineurinƒn Ab expression and NFAT nuclear abundance, due to a decrease in intracellular Na+ and Ca2+levels. The mechanism we propose to explain this antihypertrophic effect is that NHE-1 inhibition decreases intracellular Na+ levels (augmented in the hypertrophied myocardium) disfavouring the increase in intracellular Ca2+ through the NCX and therefore decreasing the Ca2+ pool involved in the activation of the prohypertrophic pathway of calcineurin /NFAT, but not in the contractile response.