UK-414,495, a selective inhibitor of neutral endopeptidase, potentiates pelvic nerve-stimulated increases in female genital blood flow in the anaesthetized rabbit.
OBJECTIVE
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)].


METHODS
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.


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 (EC(50)= 37 +/- 9 nM; 3.6 x IC(50) 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
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.
Wayman
C P
CP
Genitourinary Research Unit, Pfizer Global Research & Development, Sandwich, UK. chris.wayman@pfizer.com
Baxter
D
D
Turner
L
L
Van Der Graaf
P H
PH
Naylor
A M
AM
D000818:Animals; D001143:Arousal / Q000187:drug effects; D002987:Clitoris / Q000098:blood supply / Q000187:drug effects / Q000294:innervation; D004558:Electric Stimulation; D005260:Female; D005836:Genitalia, Female / Q000098:blood supply / Q000187:drug effects* / Q000294:innervation; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010388:Pelvis / Q000294:innervation*; D010421:Pentanoic Acids / Q000494:pharmacology*; D011817:Rabbits; D012039:Regional Blood Flow / Q000187:drug effects; D012726:Sexual Behavior, Animal / Q000187:drug effects; D013830:Thiadiazoles / Q000494:pharmacology*; D014621:Vagina / Q000098:blood supply / Q000187:drug effects / Q000294:innervation; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D010421:Pentanoic Acids; D013830:Thiadiazoles; C550955:UK-414,495; D014660:Vasoactive Intestinal Peptide; D015260:Neprilysin
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