In vitro functional responses of isolated human vaginal tissue to selective phosphodiesterase inhibitors

Abstract

Only little is known as to the significance of the cyclic nucleotide-mediated signal transduction in the control of the function of human vaginal smooth musculature. Recently, the presence of the phosphodiesterase (PDE) isoenzymes 4 (cAMP-PDE) and 5 (cGMP-PDE) in the human vagina was reported. Thus, it was the aim of the study to elucidate the effects of some PDE inhibitors on the tension induced by endothelin 1 (ET-1), as well as on levels of cGMP and cAMP in isolated human vaginal wall tissue. Using the organ bath technique, the ability of norepinephrine (NE), carbachol, serotonin (5-HT), oxytocin and ET-1 to contract isolated vaginal wall muscle strips was evaluated. In another set-up, the effects of the PDE4 inhibitor rolipram and PDE5 inhibitors sildenafil and vardenafil (1 nM-10 microM) on the tension induced by 0.1 microM ET-1 of human vaginal wall tissue strips were investigated. In order to measure drug effects on tissue levels of cGMP and cAMP, vaginal tissue was exposed to different concentrations (0.1, 1 and 10 microM) of the compounds and the accumulation of cyclic nucleotides was determined. The adenylyl cyclase stimulating agents forskolin and nitric oxide donor sodium nitroprusside (SNP) (0.01, 0.1 and 1 microM) were used as reference compounds. While NE, carbachol and oxytocin failed to contract the vaginal tissue, ET-1 and, to a certain degree, 5-HT elicited contractile responses of the isolated strip preparations. The tension induced by 0.1 microM ET-1 was dose-dependently reversed by the drugs. The rank order of efficacy was sildenafil > forskolin > rolipram >or= vardenafil > SNP. Rmax values ranged from 24% (SNP) to 50% (sildenafil). With sildenafil being the only exception, none of the compounds reached an EC50 value. The relaxing effects of the drugs were paralleled by a fourfold to tenfold increase in tissue levels of cGMP and/or cAMP. Our results demonstrate that PDE inhibitors can relax human vaginal tissue and increase levels of cyclic nucleoside monophosphates. The findings with regard to the PDE5 inhibitors may indicate that the NO-cGMP pathway is, to a certain degree, involved in the control of vaginal smooth muscle tone. This might be of significance with regard to the pharmacological treatment of disorders connected with female sexual arousal and the ability to achieve orgasm.

Morphological and Functional Changes in the Vagina following Critical Lifespan Events in the Ewe

“…Contractility of female vaginal tissue has been reported in few studies using various agents that can make smooth muscles contract (i.e., KCl, carbachol, phenylephrine, others) [43][44][45]. However, all specimens have been obtained from elder gynecological patients (hysterectomy for benign lesions or malignancy, POP) and no comparison between comparable time points during life has been performed so far.…”

Contractile Response of Human Anterior Vaginal Muscularis in Women With and Without Pelvic Organ Prolapse

“…Studies examining the in vitro contractility of human vaginal muscularis are limited. 21,22 The results of this study are an important contribution to further understand the physiological significance of the human vaginal muscularis and possible pathophysiological changes that occur with prolapse.…”

PDE5 inhibitors beyond erectile dysfunction

“…However, there are a number of other potential mechanisms by which PDE5 inhibitors may have a positive influence on heart failure, and the impact of these effects is, as yet, unclear. Therefore, despite a variety of encouraging 22 Heart failure Aortic banding in mice, 16 only minor effects in pacing induced heat failure in dogs 28 Improvement in flow-mediated vasodilatation in CHF patients 26,27 Raynaud's disease None Significant reduction in frequency and duration of Raynaud attacks 33 Cognitive dysfunction PDE5 expression profiling, [36][37][38][39] in vitro studies, 36,42 behavioral models with rodents [43][44][45][46][47] None Stroke Various stroke models in rats 42,[50][51][52][53] None Female sexual dysfunction PDE5 expression and activity in vitro [58][59][60] ; isolated organ bath 61,62 Moderate effects in pre-and post-menopausal women, [63][64][65][66] 126,127 Abbreviations: BPS, benign prostate syndrome; CHF, congestive heart failure; LUTS, lower urinary tract symptoms; PAH, pulmonary hypertension; PDE5, phosphodiesterase type-5.…”

“…[58][59][60] Organ bath experiments have demonstrated the ability of PDE5 inhibitors to relax vaginal and clitoral muscles. 61,62 Thus, it is logical to expect that PDE5 inhibitors may improve vaginal and clitoral blood flow and facilitate arousal and orgasm in women. To date, only PDE5 inhibitors beyond erectile dysfunction P Sandner et al sildenafil has been investigated clinically for effects on female sexual function.…”