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The neurovascular mechanism of clitoral erection: nitric oxide and cGMP‐stimulated activation of BK Ca channels
Author(s) -
Gragasin Ferrante S.,
Michelakis Evangelos D.,
Hogan Angie,
Moudgil Rohit,
Hashimoto Kyoko,
Wu Xichen,
Bonnet Sandra,
Haromy Al,
Archer Stephen L.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-1978com
Subject(s) - iberiotoxin , bk channel , chemistry , endocrinology , medicine , nitric oxide , cgmp specific phosphodiesterase type 5 , soluble guanylyl cyclase , cgmp dependent protein kinase , sodium nitroprusside , sildenafil , potassium channel , protein kinase a , kinase , biochemistry , cyclin dependent kinase 2 , guanylate cyclase
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 1 H‐(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.— 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 BK Ca channels. FASEB J. 18, 1382‐1391 (2004)