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

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?< 0.05), which regressed after treatment with either sildenafil or ordonafil to 5.1?± 0.1?mm and 4.8?± 0.2?mm, respectively (p?< 0.05). Phenylephrine increased neonatal rat ventricular myocyte cell surface area to 131%?± 3% of the control value, which was associated with significant increment in ERK1/2 to 143%?± 5% of the control value (p?< 0.05). Ordonafil and sildenafil decreased cell surface area to 95%?± 3% and 90%?± 1% of the control value, respectively. Both drugs decreased ERK1/2 to 88%?± 4% 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?< 0.05). For sildenafil (0.1?mg·L(-1)), calcineurin activity significantly decreased only after 24?h of incubation (22%). 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.