The effect of sildenafil on corpus cavernosal smooth muscle relaxation andcyclic GMP formation in the diabetic rabbit

Sildenafil, a type V phosphodiesterase inhibitor, enhances smooth muscle re laxation in normal human and rabbit corpus cavernosum. We investigated the in vitro effects of sildenafil on non-adrenergic, non-cholinergic and nitri c oxide (NO)-mediated cavernosal smooth muscle relaxation in diabetic rabbi ts, since alterations in this pathway are recognised in diabetic erectile d ysfunction. Diabetes mellitus was induced in male New Zealand White rabbits with alloxan, Cavernosal strips from age-matched control, 3- and 6-month d iabetic animals were mounted in organ baths. Relaxation responses to electr ical field stimulation (1-20 Hz) or sodium nitroprusside (10(-8)-10(-4) M) were assessed in the absence and presence of sildenafil (10(-8) and 10(-7) M). The effect of sildenafil on cGMP formation by the corpus cavernosum was also assessed following stimulation with sodium nitroprusside, A23187 and acetylcholine. Sodium nitroprusside-stimulated relaxations were significant ly (P < 0.03) impaired in the corpus cavernosum from both diabetic groups, (IC50 = 4.6 x 10(-6) M following 3 months of diabetes mellitus and 4.0 x 10 (-6) M following 6 months of diabetes mellitus; compared to 7.5 x 10(-7) M for pooled age-matched controls). Sildenafil (10(-7) M) significantly enhan ced sodium nitroprusside-stimulated relaxation in control (P < 0.05) and di abetic groups (P < 0.03). Electrical field stimulation-mediated relaxations of the corpus cavernosum were significantly impaired after 6-month diabete s mellitus and enhanced by sildenafil (10(-8) M). cGMP formation by the dia betic corpus cavernosum was impaired significantly, but restored towards no rmal by sildenafil. We suggest that the impairment of NO-mediated relaxatio n of the corpus cavernosum reflect, at least in part, a defect in guanylyl cyclase activity. These findings support the use of sildenafil as an effect ive, orally administered, treatment for diabetic erectile dysfunction. (C) 2001 Elsevier Science B.V. All rights reserved.