497 Dapoxetine inhibits erectile responses to stimulation of cavernous nerve in rats: A new hypothesis for its effects on ejaculation

Abstract

INTRODUCTION AND OBJECTIVES: Selective Serotonin Reuptake Inhibitors (SSRI) like paroxetine and fluoxetine are known to induce erectile dysfunction in humans and rats. Dapoxetine, a selective SSRI, is approved in Europe for the management of premature ejaculation. The aim of this study was to assess the impact of dapoxetine on (1) erectile responses induced by electrical stimulation (ES) of the cavernous nerve and (2) on smooth muscle relaxations induced by sodium nitroprusside (SNP) or sildenafil (SF) in the isolated corpus cavernosum (CC). METHODS: Wistar rats were anaesthetized with urethane. The carotid artery, penis and jugular vein were catheterized for blood pressure and intracavernous pressure recordings (BP and ICP) and drug injection, respectively. The right cavernous nerve was mounted on bipolar stimulating electrodes. ES (3, 6 and 9 Hz) were performed before and at 4, 24, 44 and 64 min after intravenous (i.v.) injection of 1 or 3 mg/kg dapoxetine or saline in 3 independent groups of 6 animals. ICP values were normalized to BP. For in vitro experiments, CC strips from Wistar rats were mounted under 0.5 g of tension in organ baths with a modified Krebs solution. After 60 min of equilibration, dapoxetine 1 mM (or its solvent) was incubated for 20 min. Strips were then exposed to norepinephrine 30 mM. When contractions reached a plateau, cumulative concentration-response curves to SNP, SF or their common solvent were constructed. RESULTS: Erectile responses were dose-dependently decreased by dapoxetine from 4 to 44 min post-dosing at all frequencies of ES. The mean of ICPmean/BP at 6 Hz was 0.47 0.01 in the 3 groups before injection. At 44 min post-injection, ICPmean/BP at 6 Hz was 0.43 0.06, 0.30 0.08 and 0.13 0.04 after vehicle, 1 mg/kg and 3 mg/kg dapoxetine (P<0.01 vs vehicle) respectively. Similar decreases were observed for ICPmax/BP. On the isolated CC, dapoxetine had no inhibitory effect on SNP or SF-mediated relaxations up to 1 mM. In addition, dapoxetine had no contractile or relaxant effects on the basal smooth muscle tone up to 10 and 100 mM, respectively CONCLUSIONS: Erectile responses were inhibited by dapoxetine at 1 and 3 mg/kg i.v. This inhibitory activity might be one of the mechanisms by which dapoxetine delays ejaculation in patients suffering from premature ejaculation. Furthermore, in vitro studies demonstrated that the inhibitory activity of dapoxetine on penile erection cannot be explained by an action at the peripheral level, suggesting a central nervous system-related mechanism.