Endothelin-1 induced hypertrophic effect in neonatal rat cardiomyocytes: involvement of Na+/H+ and Na+/Ca2+ exchangers

DULCE RA, HURTADO C, ENNIS IL, GARCIARENA CD, ALVAREZ MC, CALDIZ C, PIERCE GN, PORTIANSKY EL, CHIAPPE DE CINGOLANI GE, CAMILIóN DE HURTADO MC

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY

ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD

Año: 2006 vol. 41 p. 807 - 815

0022-2828

Endothelin-1 (ET-1) is a potent agonist of cell growth that also stimulates Na+/H+ exchanger isoform 1 (NHE-1) activity. It was hypothesized that the increase in intracellular Na+ ([Na+]i) mediated by NHE-1 activity may induce the reverse mode of Na+/Ca2+ exchanger (NCXrev) increasing intracellular Ca2+ ([Ca2+]i) which in turn will induce hypertrophy. The objective of this work was to test whether the inhibition of NHE-1 or NCXrev prevents ET-1 induced hypertrophy in neonatal rat cardiomyocytes (NRVMs). NRVMs were cultured (24 h) in the absence (control) and presence of 5 nmol/L ET-1 alone, or combined with 1 ìmol/L HOE 642 or 5 ìmol/L KB-R7943. Cell surface area, 3H-phenylalanine incorporation and atrial natriuretic factor (ANF) mRNA expression were increased to 131 ± 3, 220 ± 12 and 190 ± 25% of control, respectively (P < 0.05) by ET-1. [Na+]i and total [Ca2+]i were higher (8.1 ± 1.2 mmol/L and 636 ± 117 nmol/L, respectively) in ET-1-treated than in control NRVMs (4.2 ± 1.3 and 346 ± 85, respectively, P < 0.05), effects that were cancelled by NHE-1 inhibition with HOE 642. The rise in [Ca2+]I induced by extracellular Na+ removal (NCXrev) was higher in ET-1-treated than in control NRVMs and the effect was prevented by co-treatment with HOE 642 or KB-R7943 (NCXrev inhibitor). The ET-1-induced increase in cell area, ANF mRNA expression and 3H-phenylalanine incorporation in ET-1-treated NRVM were decreased by NHE-1 or NCXrev inhibition. Our results provide the first evidence that NCXrev is, secondarily to NHE-1 activation, involved in ET-1-induced hypertrophy in NRVMs.