FASEB J. Cell Migration Consortium
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(The FASEB Journal. 2004;18:1382-1391.)
© 2004 FASEB

The neurovascular mechanism of clitoral erection: nitric oxide and cGMP-stimulated activation of BKCa channels

FERRANTE S. GRAGASIN, EVANGELOS D. MICHELAKIS, ANGIE HOGAN, ROHIT MOUDGIL, KYOKO HASHIMOTO, XICHEN WU, SANDRA BONNET, AL HAROMY and STEPHEN L. ARCHER1

Department of Medicine (Cardiology) and the Vascular Biology Group, University of Alberta, Edmonton, Canada

1Correspondence: Cardiology Division, Department of Medicine, University of Alberta, WMC 2C2.36, 8440 112th St., Edmonton, Alberta, Canada, T6G 2B7. E-mail: sarcher{at}cha.ab.ca

Female sexual function is under-studied, and mechanisms of clitoral engorgement-relaxation are incompletely understood. Penile erection results from nitric oxide (NO) -induced cyclic guanosine monophosphate (cGMP) accumulation. cGMP-dependent protein kinase (PKG) activates large-conductance, calcium-activated potassium channels (BKCa), thereby hyperpolarizing and relaxing vascular and trabecular smooth muscle cells, allowing engorgement. We hypothesize rat clitorises relax by a similar mechanism. Rat clitorises express components of the proposed pathway: neuronal and endothelial NO synthases, soluble guanylyl cyclase (sGC), type 5 phosphodiesterase (PDE-5), and BKCa channels. The NO donor diethylamine NONOate (DEANO), the PKG activator 8-pCPT-cGMP, and the PDE-5 inhibitor sildenafil, cause dose-dependent clitoral relaxation that is inhibited by antagonists of PKG (Rp-8-Br-cGMPS) or BKCa channels (iberiotoxin). Electrical field stimulation induces tetrodotoxin-sensitive NO release and relaxation that is inhibited by the Na+ channel blocker tetrodotoxin or sGC inhibitor 1H-(1,2,4)oxadiozolo(4,3-a)quinoxalin-1-one. Human BKCa channels, transferred to Chinese hamster ovary cells via an adenoviral vector, and endogenous rat clitoral smooth muscle K+ current are activated by this PKG-dependent mechanism. Laser confocal microscopy reveals protein expression of BKCa channels on clitoral smooth muscle cells; these cells exhibit BKCa channel activity that is activated by both DEANO and sildenafil. We conclude that neurovascular derived NO causes clitoral relaxation via a PKG-dependent activation of BKCa channels. The BKCa channel is an appealing target for drug therapy of female erectile dysfunction.—Gragasin, F. S., Michelakis, E. D., Hogan, A., Moudgil, R., Hashimoto, K., Wu, X., Bonnet, S., Haromy, A., Archer, S. L. The neurovascular mechanism of clitoral erection: nitric oxide and cGMP-stimulated activation of BKCa channels.


Key Words: laser capture microdissection • protein kinase G • electrical field stimulation • sildenafil • phosphodiesterase 5 • nitric oxide electrode






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