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FASEB J. 2004 Sep;18(12):1382-91.

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

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


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 (BK(Ca)), 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 BK(Ca) 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 BK(Ca) 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 BK(Ca) 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 BK(Ca) channels on clitoral smooth muscle cells; these cells exhibit BK(Ca) 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 BK(Ca) channels. The BK(Ca) channel is an appealing target for drug therapy of female erectile dysfunction.

[Indexed for MEDLINE]

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