title: The effect of sildenafil on corpus cavernosal smooth muscle relaxation and cyclic GMP formation in the diabetic rabbit.
abstract: Sildenafil, a type V phosphodiesterase inhibitor, enhances smooth muscle relaxation in normal human and rabbit corpus cavernosum. We investigated the in vitro effects of sildenafil on non-adrenergic, non-cholinergic and nitric oxide (NO)-mediated cavernosal smooth muscle relaxation in diabetic rabbits, since alterations in this pathway are recognised in diabetic erectile dysfunction. Diabetes mellitus was induced in male New Zealand White rabbits with alloxan. Cavernosal strips from age-matched control, 3- and 6-month diabetic animals were mounted in organ baths. Relaxation responses to electrical 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 significantly (P<0.03) impaired in the corpus cavernosum from both diabetic groups, (IC(50)=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 enhanced sodium nitroprusside-stimulated relaxation in control (P<0.05) and diabetic groups (P<0.03). Electrical field stimulation-mediated relaxations of the corpus cavernosum were significantly impaired after 6-month diabetes mellitus and enhanced by sildenafil (10(-8) M). cGMP formation by the diabetic corpus cavernosum was impaired significantly, but restored towards normal by sildenafil. We suggest that the impairment of NO-mediated relaxation of the corpus cavernosum reflect, at least in part, a defect in guanylyl cyclase activity. These findings support the use of sildenafil as an effective, orally administered, treatment for diabetic erectile dysfunction.
authors.affiliation: Department of Molecular Pathology and Clinical Biochemistry, Royal Free Hospital and University College Medical School, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. c.thompson@rfc.ucl.ac.uk
authors.forename: C S
authors.initials: CS
authors.lastname: Thompson
authors.forename: F H
authors.initials: FH
authors.lastname: Mumtaz
authors.forename: M A
authors.initials: MA
authors.lastname: Khan
authors.forename: R M
authors.initials: RM
authors.lastname: Wallis
authors.forename: D P
authors.initials: DP
authors.lastname: Mikhailidis
authors.forename: R J
authors.initials: RJ
authors.lastname: Morgan
authors.forename: G D
authors.initials: GD
authors.lastname: Angelini
authors.forename: J Y
authors.initials: JY
authors.lastname: Jeremy
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001835:Body Weight; D000001:Calcimycin / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000503:physiopathology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D010413:Penis / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D011817:Rabbits; D000068677:Sildenafil Citrate; D013450:Sulfones; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D020030:Nitric Oxide Donors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D009599:Nitroprusside; D000001:Calcimycin; D000068677:Sildenafil Citrate; D006152:Cyclic GMP; D000109:Acetylcholine