The neurovascular mechanism of clitoral erection: nitric oxide and cGMP‐stimulated activation of BK_Cachannels

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.

Ca2+‐activated K+ channel (KCa) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction

“…These reports are consistent with the present findings of the contribution of KCa to PDE5 inhibitor-induced vasodilatation of HPRA. The lack of influence of KCa blockade on relaxations driven by PDE5 inhibition in HCC is, however, in contradiction to the previously reported sensitivity of sildenafil-induced relaxation to IbTx in HCC (Kun et al, 2009), and the suggested participation of KCa in PDE5 inhibitor-induced relaxation in rabbit clitoris (Gragasin et al, 2004) and mouse corpus cavernosum (Werner et al, 2008). Our results nevertheless were strengthened by the absence of significant effects of NS-8 or NS1619 on sildenafil-induced relaxation of HCC.…”

“…Previous studies carried out in different tissues, including erectile tissues, have described intracellular activation of KCa by cGMP generated in smooth muscle, contributing to NO/cGMP-mediated relaxation (Sausbier et al, 2000;Lee and Kang, 2001;Gragasin et al, 2004;Tanaka et al, 2004). It has been proposed that the cGMP-induced activation of BK channels is mediated by cGMP-dependent kinase (Schubert and Nelson, 2001;Zhou et al, 2001).…”

The Impact of Metabolic Syndrome and Its Components on Female Sexual Dysfunction: A Narrative Mini-Review

“…Female sexual function showed a combination of endocrine, vascular and neuromuscular factors that regulate important steps of female sexual reaction as increased genital blood flow, enlarged clitoral diameter and length, increased vaginal luminal diameter and lubrication, wall engorgement [59,60]. …”

“…Pelvic vascular injury and neuropathy induced by some metabolic factors as dyslipidemia, glucose intolerance, insulin resistance, diabetes mellitus, and systemic arterial hypertension could cause clitoral insufficiency and reduced vaginal engorgement resulting in vasculogenic FSD [37,59,60,61,62,63]. In particular obesity, as the result of excessive accumulation of body fat, is strongly associated with MS.…”

Recognising female sexual dysfunction as an essential aspect of effective diabetes care

“…Research into the arterial blood supply supplying the female pelvic anatomy relating to the presence of atherosclerosis of the arterial bed can lead to decreased vaginal engorgement and clitoral insufficiency syndrome resulting in vasculogenic FSD (Doumas et al, 2005, Gragasin et al, 2004. Additionally the prevalence of Metabolic Syndrome increases during the fifth and sixth decades of women's lives and also coincides with the onset of the menopause hence associated with the lower oestrogenic milieu which enhances risk factors for metabolic syndrome such as increased insulin resistance, obesity and hyperglycaemia (Otunctemur et al, 2014).…”