Cyclic Guanosine Monophosphate-specific Phosphodiesterase Research Articles

Purpose The effects of sildenafil, a highly selective inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase type 5, on erectile function in the anesthetized dog were evaluated. Materials and Methods In pentobarbital-anesthetized dogs, increases in intracavernosal pressure in the corpus cavernosum and penile blood flow were induced by pelvic nerve stimulation over a frequency range of 1 to 16 hertz. The effects of increasing doses of sildenafil on electrically stimulated intracavernosal pressure, penile blood flow, blood pressure, and heart-rate were evaluated. In parallel experiments, the effects of the nitric oxide synthase inhibitor N omega-Nitro-L-Arginine (L-NOArg) on these same parameters also were assessed. Results The effects of nerve stimulation on intracavernosal pressure and blood flow to the penis were blocked by L-NOArg, 0.1-3 mg./kg., in a dose-related manner, confirming the important role of nitric oxide in producing erections. Sildenafil, 1-100 micro g./kg administered intravenously, had no direct effect on intracavernosal pressure but potentiated the increase in intracavernosal pressure induced by nerve stimulation. This potentiation occurred at sildenafil plasma concentrations consistent with its relaxation effect on isolated human cavernosal tissue and its inhibition of phosphodiesterase type 5 in vitro. Sildenafil had no significant effect on blood pressure or heart rate. Conclusions By inhibiting cyclic guanosine monophosphate-specific phosphodiesterase type 5, sildenafil augments the neuronal mechanism responsible for penile erection. This mechanism explains the significant improvements reported in the rigidity and duration of erections seen in patients with erectile dysfunction who have been treated with oral sildenafil.

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