title: The neurovascular mechanism of clitoral erection: nitric oxide and cGMP-stimulated activation of BKCa channels.
abstract: 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.
authors.affiliation: Department of Medicine (Cardiology) and the Vascular Biology Group, University of Alberta, Edmonton, Canada.
authors.forename: Ferrante S
authors.initials: FS
authors.lastname: Gragasin
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
authors.forename: Angie
authors.initials: A
authors.lastname: Hogan
authors.forename: Rohit
authors.initials: R
authors.lastname: Moudgil
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Xichen
authors.initials: X
authors.lastname: Wu
authors.forename: Sandra
authors.initials: S
authors.lastname: Bonnet
authors.forename: Al
authors.initials: A
authors.lastname: Haromy
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002987:Clitoris / Q000033:anatomy & histology / Q000098:blood supply / Q000294:innervation / Q000502:physiology*; D006224:Cricetinae; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004558:Electric Stimulation; D004594:Electrophysiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels; D007834:Lasers; D042282:Microdissection; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000098:blood supply / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics / Q000378:metabolism*; D011687:Purines; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D013450:Sulfones
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D010879:Piperazines; D024681:Potassium Channels, Calcium-Activated; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D002118:Calcium