Vardenafil and sildenafil are potent and specific phosphodiesterase type 5 (PDE 5) inhibitors. In human penile cavernosal smooth muscle cells, we have previously shown that vardenafil has a lower biochemical inhibition constant (Ki) than sildenafil. In this study, we compared the efficacy of vardenafil and sildenafil in facilitating penile erection in a rabbit model. Penile erections were elicited by submaximal (2.5 or 6 Hz) pelvic nerve stimulation (PNS) repeated every 5 minutes for 30 minutes with or without intravenous (i.v.) administration of vardenafil (1-30 microg/kg) or sildenafil (10-30 microg/kg). Erectile response was assessed by continuously recording intracavernosal pressure (ICP) and systemic arterial pressure (SAP). All data were expressed as a ratio of ICP:SAP. I.v. administration of either PDE 5 inhibitor facilitated PNS-induced erection and increased ICP:SAP in a dose-dependent manner, reaching peak response at approximately 5 minutes. However, the threshold dose at which facilitation of erection occurred was lower for vardenafil (3 microg/kg) than for sildenafil (10 microg/kg). At the 10-microg/kg dose (i.v.), the response duration was significantly greater with vardenafil (169 +/- 23 seconds) than with sildenafil (137 +/- 31 seconds). Direct intracavernosal (i.c.) injection of 1-30 microg/kg vardenafil or sildenafil also caused dose-dependent increases in ICP:SAP in the absence of PNS. Response durations increased in a dose-dependent manner and lasted more than 5 times that of i.v. drug administration coupled with PNS. Irrespective of the route of administration (i.c. or i.v.), at equivalent doses, vardenafil was significantly more efficacious than sildenafil in facilitating pelvic nerve-mediated penile erection and in eliciting erection in the absence of PNS. The increases in ICPs occurred more quickly, were of larger magnitude, and were sustained for longer durations for vardenafil than for sildenafil. On the basis of the biochemical data and physiological responses from this study, further clinical evaluation of vardenafil as treatment for erectile dysfunction is warranted.