ORIGINAL RESEARCH—BASIC SCIENCE Influence of Sildenafil on Micturition and Urethral Tone in Ovariectomized and Non-ovariectomized Mice Xavier Gamé, MD,* †‡ Ourdia Bouali, MD, ‡ Julien Allard, MD, † Pierre Gourdy, MD, PhD, † Ghislaine Escourrou, MD, § Ivan Tack, MD, PhD, † Pascal Rischmann, MD,* Jean-François Arnal, MD, PhD, † and Bernard Malavaud, MD, PhD* *Service d’Urologie, Transplantation Rénale et Andrologie, Centre Hospitalier Universitaire Rangueil, Toulouse, France; † Institut National de la Santé et de la Recherche Médicale U858 et Laboratoire de Physiologie, Toulouse, France; ‡ Institut Fédératif de Recherche 31, Centre Hospitalier Universitaire Rangueil, Toulouse, France; § Laboratoire D’Anatomie Pathologique, Centre Hospitalier Universitaire Rangueil, Toulouse, France DOI: 10.1111/j.1743-6109.2011.02559.x ABSTRACT Introduction. Nitric oxide synthases (NOSs) and estrogen receptors are expressed in the female urethra. Aim. We aimed to assess the impact of sildenafil on micturition behavior, urethral tone according to the hormonal status and to determine the implications of the neuronal isoform of NOS (nNOS). Methods. Four-week-old C57/BL6 female mice were sham-operated or ovariectomized. Six weeks later, they were injected intraperitoneally by any combination of sildenafil, 7-nitroindazole (7-NI)—a potent selective nNOS inhibitor—or the corresponding vehicles. The mice were then subjected to micturition behavior and leak point pressure studies. Urethral histomorphometry was performed. Main Outcome Measures. The main outcome measures were micturition behavior, leak point pressure, and histomorphometry. Results. In sham-operated and ovariectomized animals, sildenafil did not impact micturition, although it decreased urethral resistance 10-fold. nNOS inhibition by 7-NI reduced the number of micturitions and increased residual volume and leak point pressure. It abrogated sildenafil-induced drop in urethral resistances. Hormonal status did not influence the structure of the urethral layers. Conclusions. Irrespective of the hormonal status, sildenafil decreased leak point pressure by a nNOS-mediated mechanism. Gamé X, Bouali O, Allard J, Gourdy P, Escourrou G, Tack I, Rischmann P, Arnal J-F, and Malavaud B. Influence of sildenafil on micturition and urethral tone in ovariectomized and non- ovariectomized mice. J Sex Med 2012;9:466–471. Key Words. Sildenafil; Urethra, Physiology; Nitric Oxide; Neuronal Nitric Oxide Synthase; Micturition; Leak Point Pressure; Urethral Tone Introduction A utonomic regulation of the lower urinary tract is driven by all three components of the autonomic nervous system. Produced by the three isoforms of nitric oxide synthase (NOS) that is the neuronal isoform of NOS (nNOS), the endothelial isoform (eNOS), and the inducible isoform (iNOS); nitric oxide (NO) is the key neurotrans- mitter of the nonadrenergic, noncholinergic nerves of the peripheral nervous system [1]. The main isoform of the lower urinary tract is nNOS, located in the nerves supplying the smooth muscle layers of the urethral wall. It is only sparsely present in the detrusor muscle [2]. NOS isoforms regulation by estrogens is organ-dependent. Castration decreases nNOS and eNOS expression in the vagina while 466 J Sex Med 2012;9:466–471 © 2011 International Society for Sexual Medicine