Sildenafil Effect on the Human Bladder Involves the L-cysteine/Hydrogen Sulfide Pathway: A Novel Mechanism of Action of Phosphodiesterase Type 5 Inhibitors

Background: Phosphodiesterase type 5 inhibitors (PDE5-Is) are effective in the treatment of lower urinary tract symptom (LUTS), although their mechanism of action is still unclear. PDE5-Is cause bladder detrusor relaxation, and this effect is partially independent of nitric oxide. Hydrogen sulfide (H2S) is a newly discovered transmitter with myorelaxant properties. It is predominantly formed from L-cysteine by cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE). Objective: To evaluate whether the L-cysteine/H2S pathway contributes to the relaxing effect of sildenafil on the human detrusor dome. Design, setting, and participants: Samples of bladders obtained from men undergoing open prostatectomy for benign prostatic hyperplasia (BPH) were used. The presence of CBS and CSE enzymes was assessed by western blot. H2S production was measured by a colorimetric assay in basal and stimulated conditions with L-cysteine and in response to sildenafil (1, 3, 10, and 30 mu M), 8-bromo-cyclic guanosine monophosphate (8-bromo-cGMP; 100 mu M) or dibutyryl-cyclic adenosine monophosphate (dibutyryl-cAMP; 100 mu M). A curve concentration effect of sodium hydrosulfide (NaHS), H2S donor (0.1 mu M to 10 mM), L-cysteine (0.1 mu M to 10 mM), and sildenafil (0.1-10 mu M) was performed on precontracted detrusor dome strips. To investigate H2S signaling in a sildenafil effect, CBS and CSE inhibitors were used. Outcome measurements and statistical analysis: Analysis of variance was used, followed by the Bonferroni post hoc test. Results and limitations: CBS and CSE are present in the human bladder dome and efficiently convert L-cysteine into H2S. Both NaHS and L-cysteine relaxed human strips. Sildenafil caused (1) a relaxation of bladder dome strips and (2) a concentration-dependent increase in H2S production. Both effects were significantly reduced by CBS and CSE inhibitors. Similar to sildenafil, both 8-bromo-cGMP and dibutyryl-cAMP caused an increase in H2S production. Conclusions: The sildenafil relaxant effect on the human bladder involves the H2S signaling pathway. This effect may account in part for the efficacy of PDE5-Is in LUTS. A better definition of the pathophysiologic role of the H2S pathway in the human bladder may open new therapeutic approaches. (C) 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.