A major cause of female sexual arousal disorder (FSAD) is thought to be decreased genital blood flow - this is manifested as reduced vaginal, labial and clitoral engorgement (Goldstein, 1998; Berman, 1999). Treatment of women with FSAD maybe achievable by restoration of the normal sexual arousal response via enhancing genital blood flow. Vasoactive intestinal peptide (VIP), neuropeptide Y and nitric oxide are the principal vasoactive neurotransmitters found in the vasculature of the vagina (Hoyle, 1996). Neutral endopeptidase EC3.4.24.11 (NEP) modulates the activity of a number of bioactive peptides including VIP (Duggan, 1995). The aim of this study was to investigate the role of NEP in the control of female genital blood flow using a novel, potent and selective NEP inhibitor ((R)-2-({1-[(5-ethyl-1,3,4-thiadiazol-2-yl)carbamoyl]cyclopentyl}methyl)valeric acid; UK414,495, NEPi;) potency versus rabbit isolated NEP IC₅₀=10.2nM).

Experiments were in compliance with UK legislation and subject to local ethical review. Experiments were carried out in female New Zealand rabbits (~2.5kg) under anaesthesia without recovery (sedation with Medetomidine/Ketamine at 0.5 & 0.25ml.kg^-1 i.m. respectively, anaesthesia with 2% Isoflurane with O₂ at 2l.min^-1). Vaginal blood flow (VBF) was monitored using laser Doppler probes (1mm diameter). Increases in VBF were induced by either electrical stimulation of the pelvic nerve (5V, 0.5ms, 10s, 2-16Hz every 15 minutes) or by i.v. infusion of VIP (60ug/kg). NEPi was either intravenously infused to give steady state plasma concentrations of 10-1029nM, equivalent to 1-100xIC₅₀ NEP, or applied topically into the vagina (0.2mg/ml). Data is expressed as mean ± s.e.m, significant differences were assessed using an unpaired Student's t-test.

Stimulation of the pelvic nerve (PN) induces increases in VBF, compared to basal flow (28.2±1.2 versus 6.4 ± 0.4ml/min/100g tissue, n=42). These increases can be mimicked by infusion of exogenous VIP (14.6±1.2 ml/min/100g tissue, n=6). Pre-treatment with NEPi dose-dependently enhances PN-stimulated increases in VBF (EC₅₀=37.0±8.9nM; n=10). This dose is equivalent to 3.6xIC₅₀ for native rabbit NEP. The maximal enhancement (50.3±9.5%) was observed at a concentration of 105nM or above. Pre-treatment with NEPi (558nM) significantly enhances the amplitude (111±37%, n=6) and area-under-curve (123±50%; n=6) of VIP-induced increases in VBF. Intra-vaginal topical application of NEPi enhanced PN stimulated increases 78±13% in VBF at 60min post dose. NEPi has no effect on basal/unstimulated VBF and no effects on cardiovascular parameters.

This study demonstrates that inhibition of NEP enhances genital blood flow in the anaesthetised rabbit. NEPi has no effects on basal (unstimulated) genital blood flow indicating that NEP inhibitors are unlikely to induce sexual arousal in the absence of sexual stimulation. Inhibition of NEP is a potential mechanism to treat FSAD via enhancement of endogenous vasorelaxant mechanisms, thereby restoring normal arousal.

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