In vivo analysis of chronic phosphodiesterase-5 inhibition with sildenafil in penile erectile tissues: No tachyphylaxis effect

Purpose: Conflicting information exists regarding the long-term efficacy of phosphodiesterase-5 (PDE5) inhibitor therapy for erectile dysfunction, particularly in regard to whether therapeutic resistance occurs. We investigated the erectile response, and cavernous PDE5 expression and activity after continuous long-term administration of sildenafil at verified therapeutic plasma concentrations, applying an in vivo rat model of age related erectile dysfunction. Materials and Methods: Male Fisher 344 young (4 months old) and aged (19 months old) rats (National Institute of Aging, Bethesda, Maryland) were injected with sildenafil mesylate (20 mg/kg) or saline subcutaneously every 8 hours for 3 weeks. After a 10 to 18-hour washout period electrical stimulation of the cavernous nerve was performed to assess penile erection. Penes were excised to measure PDE5 protein expression and activity, and blood was collected for sildenafil measurement. Responses were compared with those determined 30 minutes after a single sildenafil injection. Results: Chronic sildenafil treatment increased the detumescence phase in young and aged rats (p <0.05), although aged rats showed a greater increase than young rats. Baseline cavernous PDE5 expression and activity were greater in aged vs young rats (p <0.05). After chronic sildenafil treatment cavernous PDE5 expression was increased in young (p <0.05) but not in aged rats. Chronic and acute sildenafil treatment similarly inhibited PDE5 activity in the penis of young and aged rats (p <0.05), coincident with its free plasma concentrations equivalent to clinically therapeutic ranges. Conclusions: Pharmacological PDE5 inhibitor therapy with sildenafil chronically does not result in treatment resistance. Rather, therapeutic efficacy is maintained and apparently more pronounced with erectile impairment than with normal erectile ability.