The ability of phosphodiesterase-5 inhibitors sildenafil and ordonafil to reverse L-NAME induced cardiac hypertrophy in the rabbit: Possible role of calcineurin and p38

Abstract

Phosphodiesterase 5 inhibitors (PDE-5Is) can suppress and (or) reverse pressure overload induced myocardial hypertrophy. This study investigated the suppressive effect of 2 PDE-5Is (sildenafil and ordonafil) on N-nitro-L-arginine methyl ester (L-NAME)-induced cardiac hypertrophy in rabbit heart, and examined their possible mechanism of action. L-NAME increased left ventricular thickness to 6.1± 0.18 mm from 4.6 ± 0.13 mm (p andlt; 0.05), which regressed after treatment with either sildenafil or or-donafil to 5.1 ± 0.1 mm and 4.8 ± 0.2 mm, respectively (p andlt; 0.05). Phenylephrine increased neonatal rat ventricular myocyte cell surface area to 131percent ± 3percent of the control value, which was associated with significant increment in ERK1-2 to 143percent ± 5percent of the control value (p andlt; 0.05). Ordonafil and sildenafil decreased cell surface area to 95percent ± 3percent and 90percent ± 1percent of the control value, respectively. Both drugs decreased ERK1-2 to 88percent ± 4percent of the control value. Calcineurin activity was significantly decreased after 1 h of treatment with 0.1 mg·L-1 ordonafil (1.15 ± 0.05, p andlt; 0.05). For sildenafil (0.1 mg·L-1), calcineurin activity significantly decreased only after 24 h of incubation (22percent). Also p38 activation was attenuated by ordonafil and sildenafil (0.1 mg·L-1). It is suggested that both drugs have the ability to reverse L-NAME-induced cardiac hypertrophy and suppress phenylphrine-induced myocyte hypertrophy, and that these effects may be mediated through the attenuation of calcineurin and its downstream signaling pathways (p38) in neonatal rat ventricular myocytes.