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

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 H-1-(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.