| UK-414,495, a selective inhibitor of neutral endopeptidase, potentiates pelvic nerve-stimulated increases in female genital blood flow in the anaesthetized rabbit. | |
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MedLine Citation:
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PMID: 20412068 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 (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 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. |
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Authors:
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C P Wayman; D Baxter; L Turner; P H Van Der Graaf; A M Naylor |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: British journal of pharmacology Volume: 160 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-04-23 Completed Date: 2010-07-26 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 51-9 Citation Subset: IM |
Affiliation:
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Genitourinary Research Unit, Pfizer Global Research & Development, Sandwich, UK. chris.wayman@pfizer.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Arousal / drug effects Clitoris / blood supply, drug effects, innervation Electric Stimulation Female Genitalia, Female / blood supply, drug effects*, innervation Neprilysin / antagonists & inhibitors* Pelvis / innervation* Pentanoic Acids / pharmacology* Rabbits Regional Blood Flow / drug effects Sexual Behavior, Animal / drug effects Thiadiazoles / pharmacology* Vagina / blood supply, drug effects, innervation Vasoactive Intestinal Peptide / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Pentanoic Acids; 0/Thiadiazoles; 0/UK-414,495; 37221-79-7/Vasoactive Intestinal Peptide; EC 3.4.24.11/Neprilysin |
| Comments/Corrections | |
Comment In:
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Br J Pharmacol. 2010 May;160(1):48-50
[PMID:
20412067
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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