Initial characterization of hydrogen sulfide effects in female sexual function.

Introduction: In our male animal models, hydrogen sulfide (H(2)S) displayed significant vasodilatory and smooth muscle relaxant effects suggestive of an endogenous physiological role in erectile process.

Aim: In this first exploratory study, we aimed to identify the existence and mechanism of H(2)S pathway in female sexual physiology.

Methods: Vaginal and clitoral cavernosal smooth muscle strips from New Zealand white rabbits (N = 12) were exposed to stable H(2)S donor, sodium hydrosulfide hydrate (NaHS.xH(2)O, 100 microM-1.6 mM), in isometric tension studies. The NaHS responses were repeated after incubations with (i) N(omega)-nitro-L-arginine (50 microM), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 microM) or cis-N-[2-phenylcyclopentyl]-azacyclotridec-1-en-2-amine (MDL 12,330A) (10 microM); and (ii) potassium chloride medium (high K(+) 60 mM/low K(+) 10 mM), tetraethylammonium (10 mM) or glibenclamide (100 microM). Relaxant effect of NaHS was also compared with those of nitroglycerine (0.18-78.2 microM) and sildenafil (0.084-25.3 microM). Additionally, samples (N = 16) were collected for estimations of plasma and tissue H(2)S and expression levels of cystathionine gamma-lyase (CSE) and cystathionine beta-synthase (CBS) proteins.

Main Outcome Measures: In vitro evidences for H(2)S formation and its physiopharmacological effects.

Results: NaHS produced significant concentration-dependent relaxation of vaginal and cavernosal smooth muscles with inhibitions by combination of ODQ and MDL 12,330A (26.4%), N(omega)-nitro-L-arginine (22.2%), high K(+) (15.1%) or glibenclamide (10.1%). Based on molar potency, NaHS was 18.3 and 6.3 times weaker than nitroglycerine and sildenafil, respectively. Quantitative assays indicated that plasma H(2)S level was 16.5 +/- 2.58 microM, and H(2)S was synthesized in the clitoral and vaginal smooth muscles (1.8 and 3.9 nmol/mg soluble protein compared with 26.5 nmol/mg in the liver: positive control). Similarly, western blotting identified the protein expression bands of CSE (44.5 kDa) and CBS (63 kDa) in these genital tissue samples.

Conclusion: These pilot studies clearly indicate the smooth muscle relaxant effect of H(2)S in female genital tract, mediating through cyclic adenosine 3':5'-monophosphate, nitric oxide-cyclic guanosine monophosphate and K(+)(ATP) channels. Taken together with biochemical and molecular evidences for endogenous formation, H(2)S pathway could be a contributing factor in female sexual responses.