UK‐414,495, a selective inhibitor of neutral endopeptidase, potentiates pelvic nerve‐stimulated increases in female genital blood flow in the anaesthetized rabbit

• Published in: British journal of pharmacology 2010-05, Vol.160 (1), p.51-59
• Main Authors: Wayman, CP, Baxter, D, Turner, L, Van Der Graaf, PH, Naylor, AM
• Format: Article
• Language: English
• Subjects: Animals; Arousal - drug effects; Cerebral blood flow; Clitoris - blood supply; Clitoris - drug effects; Clitoris - innervation; Electric Stimulation; Electrical stimuli; Female; female sexual arousal; Genitalia; Genitalia, Female - blood supply; Genitalia, Female - drug effects; Genitalia, Female - innervation; laser Doppler; Lasers; Neprilysin; Neprilysin - antagonists & inhibitors; Neuropeptide Y; Neurotransmitters; neutral endopeptidase; Nitric oxide; pelvic nerve; Pelvis; Pelvis - innervation; Pentanoic Acids - pharmacology; rabbit; Rabbits; Regional Blood Flow - drug effects; Research Paper with; Sexual behavior; Sexual Behavior, Animal - drug effects; Thiadiazoles - pharmacology; Vagina; Vagina - blood supply; Vagina - drug effects; Vagina - innervation; vaginal blood flow; valeric acid; Vasoactive intestinal peptide; Vasoactive Intestinal Peptide - pharmacology; vasocongestion; VIP
• ISSN: 0007-1188; 1476-5381; 1476-5381
• DOI: 10.1111/j.1476-5381.2010.00691.x

Background and purpose:  Female sexual arousal consists of a number of physiological responses resulting from increased genital blood. Vasoactive intestinal peptide (VIP), neuropeptide Y and to a lesser extent nitric oxide are neurotransmitters found in the vasculature of the genitalia. Neutral endopeptidase (NEP) modulates the activity of neuropeptides including VIP. The aim of this study was to investigate the control of genital blood flow by VIP and endogenous neuropeptides using a selective NEP inhibitor [UK‐414,495, ((R)‐2‐({1‐[(5‐ethyl‐1,3,4‐thiadiazol‐2‐yl) carbamoyl]cyclopentyl}methyl) valeric acid)]. Experimental approach:  Vaginal and clitoral blood flow (VBF and CBF) were monitored using laser Doppler in terminally anaesthetized New Zealand rabbits. Increases in VBF and CBF were induced by either electrical stimulation of the pelvic nerve or by i.v. infusion of VIP. Key results:  Stimulation of the pelvic nerve increased VBF and CBF, compared with basal flow. Increases were mimicked by infusion of exogenous VIP. UK‐414,495 dose‐dependently potentiated pelvic nerve‐stimulated increases in VBF (EC50= 37 ± 9 nM; 3.6 × IC50 rabbit NEP). Nerve‐stimulated increases in VBF and CBF were both enhanced after UK‐414,495. UK‐414,495 increased the amplitude and duration of VIP‐induced increases in VBF. UK‐414,495 had no effect on basal VBF or cardiovascular parameters. Conclusions and implications:  Inhibition of NEP potentiates pelvic nerve‐stimulated increases in genital blood flow. This suggests that the endogenous neurotransmitter mediating genital blood flow is a substrate for NEP (most likely VIP). NEP inhibitors may restore sexual arousal in women adversely affected by female sexual arousal disorder. This article is commented on by Angulo, pp. 48–50 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00693.x