OBJECTIVESSildenafil is a widely-prescribed effective on-demand treatment of erectile dysfunction (ED). Chronic treatment with sildenafil could help patients with ED.METHODSThe effects of an 8-week long treatment with sildenafil (60 mg/kg/d sc) in male Sprague Dawley rats were evaluated on electrically-elicited erectile responses in vivo before and after an acute injection of sildenafil (0.3mg/kg iv). In addition, endothelium-dependent and -independent relaxations of strips of corpus cavernosum in vitro were examined. All experiments were performed 36 hours after the last injection of sildenafil.RESULTSEndothelium-dependent relaxations of cavernosal strips to acetylcholine were enhanced after chronic treatment with sildenafil while relaxations to A23187 or sodium nitroprusside were unchanged. Frequency-dependent erectile responses elicited by cavernous nerve stimulation were significantly improved. Moreover, the erectile responses to acute sildenafil were greater in chronically-treated rats with sildenafil.CONCLUSIONSThis is the first report providing experimental support for chronic dosing with sildenafil which could be of use for patients that are poor responders to on-demand treatment. Chronic sildenafil may regulate the transduction pathway leading to the activation of eNOS but has no effect on NO bioavailability or on the cGMP pathway, thereby eliminating a possible concern for tachyphylaxis.