title: UK-414,495, a selective inhibitor of neutral endopeptidase, potentiates pelvic nerve-stimulated increases in female genital blood flow in the anaesthetized rabbit.
abstract: 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.
authors.affiliation: Genitourinary Research Unit, Pfizer Global Research & Development, Sandwich, UK. chris.wayman@pfizer.com
authors.forename: C P
authors.initials: CP
authors.lastname: Wayman
authors.forename: D
authors.initials: D
authors.lastname: Baxter
authors.forename: L
authors.initials: L
authors.lastname: Turner
authors.forename: P H
authors.initials: PH
authors.lastname: Van Der Graaf
authors.forename: A M
authors.initials: AM
authors.lastname: Naylor
mesh_terms: 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
chemical_list: D010421:Pentanoic Acids; D013830:Thiadiazoles; C550955:UK-414,495; D014660:Vasoactive Intestinal Peptide; D015260:Neprilysin
references.citation: Eur J Clin Invest. 1983 Aug;13(4):321-4
references.pmid: 6413218
references.citation: Nat Rev Urol. 2009 Apr;6(4):216-22
references.pmid: 19352396
references.citation: Eur Urol. 2000 Jul;38(1):20-9
references.pmid: 10859437
references.citation: Br J Pharmacol. 2008 Sep;155(2):236-43
references.pmid: 18587425
references.citation: J Urol. 2003 Dec;170(6 Pt 1):2333-8
references.pmid: 14634409
references.citation: Int J STD AIDS. 2007 Feb;18(2):130-1
references.pmid: 17331290
references.citation: J Anat. 1996 Jun;188 ( Pt 3):633-44
references.pmid: 8763480
references.citation: FASEB J. 1997 Apr;11(5):355-64
references.pmid: 9141502
references.citation: Am J Physiol. 1996 Aug;271(2 Pt 2):R393-7
references.pmid: 8770140
references.citation: Int J Impot Res. 1999 Sep;11 Suppl 1:S31-8
references.pmid: 10554927
references.citation: Clin Sci (Lond). 1995 Sep;89(3):267-71
references.pmid: 7493422
references.citation: Int J Impot Res. 1997 Mar;9(1):27-37
references.pmid: 9138056
references.citation: Fertil Steril. 2006 May;85(5):1496-501
references.pmid: 16579999
references.citation: J Urol. 1997 Jul;158(1):75-8
references.pmid: 9186326
references.citation: J Urol. 2004 Mar;171(3):1357-61
references.pmid: 14767348
references.citation: J Psychosom Obstet Gynaecol. 2006 Mar;27(1):31-41
references.pmid: 16752874
references.citation: Int J Impot Res. 2005 Dec;17 Suppl 1:S44-51
references.pmid: 16391543
references.citation: Br J Pharmacol. 2002 Jan;135(2):546-54
references.pmid: 11815390
references.citation: Mol Cell Biol Res Commun. 1999 Aug;2(2):131-7
references.pmid: 10542137
references.citation: World J Urol. 2005 Dec;23(6):398-404
references.pmid: 16273419
references.citation: Urology. 2000 Jun;55(6):812-5
references.pmid: 10840082
references.citation: Urology. 2005 Mar;65(3):604-10
references.pmid: 15780401
references.citation: Int J Impot Res. 2003 Apr;15(2):137-41
references.pmid: 12789394
references.citation: J Sex Marital Ther. 2001 Oct-Dec;27(5):411-20
references.pmid: 11554201
references.citation: J Sex Med. 2006 Nov;3(6):988-995
references.pmid: 17100931
references.citation: Int J Impot Res. 1998 May;10 Suppl 2:S84-90; discussion S98-101
references.pmid: 9647967
references.citation: Peptides. 1987 Sep-Oct;8(5):797-800
references.pmid: 3432128
references.citation: Peptides. 1999;20(5):539-43
references.pmid: 10465504
references.citation: J Sex Marital Ther. 1999 Apr-Jun;25(2):137-44
references.pmid: 10327383
references.citation: Int J Impot Res. 1998 May;10 Suppl 2:S104-6; discussion S124-5
references.pmid: 9647970
references.citation: J Med Chem. 2006 Jul 13;49(14):4409-24
references.pmid: 16821800
references.citation: BJOG. 2003 Nov;110(11):1014-24
references.pmid: 14592587
references.citation: Br J Pharmacol. 2009 Jun;157(4):527-36
references.pmid: 19630832
references.citation: Am J Obstet Gynecol. 1982 Jun 15;143(4):414-20
references.pmid: 7201240
references.citation: Int J Impot Res. 2000 Sep;12 Suppl 3:S32-9
references.pmid: 11002397
references.citation: Br J Pharmacol. 2008 Mar;153(6):1105-19
references.pmid: 17965745
references.citation: Br J Pharmacol. 2008 Mar;153 Suppl 2:S1-209
references.pmid: 18347570
references.citation: JAMA. 1999 Feb 10;281(6):537-44
references.pmid: 10022110
references.citation: Biochem Pharmacol. 1997 Aug 15;54(4):509-15
references.pmid: 9313778
references.citation: Urology. 1999 Sep;54(3):385-91
references.pmid: 10475340
references.citation: Exp Clin Endocrinol. 1991;98(2):61-9
references.pmid: 1778234