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

Abstract

BackgroundPhosphodiesterase 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-β-synthase (CBS) and cystathionine-γ-lyase (CSE). ObjectiveTo evaluate whether the L-cysteine/H2S pathway contributes to the relaxing effect of sildenafil on the human detrusor dome. Design, setting, and participantsSamples 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 30μM), 8-bromo–cyclic guanosine monophosphate (8-bromo–cGMP; 100μM) or dibutyryl–cyclic adenosine monophosphate (dibutyryl-cAMP; 100μM). A curve concentration effect of sodium hydrosulfide (NaHS), H2S donor (0.1μM to 10mM), L-cysteine (0.1μM to 10mM), and sildenafil (0.1–10μM) 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 analysisAnalysis of variance was used, followed by the Bonferroni post hoc test. Results and limitationsCBS 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. ConclusionsThe 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.