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Background and purpose: The mechanism(s) of action responsible for the beneficial effects of phosphodiesterase 5 (PDE5) inhibitors including sildenafil on lower urinary tract symptoms suggestive of benign prostate hyperplasia are unclear. In particular, the role of the NO-cGMP signalling pathway in regulating human bladder dome smooth muscle relaxation is questionable. Thus, we assessed the ability of a PDE5 inhibitor, sildenafil, to relax such tissue, and identified the signalling pathways involved in this relaxation. Experimental approach: Human bladder samples were obtained from 20 patients with no overactive bladder undergoing cystectomy for bladder cancer. Detrusor strips were mounted isometrically in Krebs-HEPES solution. Concentration-response curves for sildenafil (10 nM-30 mM) were generated in the presence of various inhibitors on carbachol-induced pre-contraction. Key results: Sildenafil relaxed carbachol-pre-contracted human detrusor strips, starting at 3 mM. This effect was not modified by NO donors, S-nitroso-N-acetylpenicillamine (10 mM) or sodium nitroprusside (300 nM), but was significantly inhibited by inhibition of guanylate cyclase (with ODQ, 10 mM) or adenylyl cyclase (with MDL-12,330A, 10 mM), by the ATP-sensitive potassium channel inhibitor, glibenclamide (10 mM), or inhibition of the large (with iberiotoxin, 30 nM) or small (with apamin, 100 nM) conductance calcium-activated potassium channels. Conclusions and implications:Sildenafil-induced relaxation of human detrusor smooth muscle involved cGMP-, cAMP-and K + channel-dependent signalling pathways, with a minor contribution from NO. The effect of this sildenafil-induced relaxation on the clinical benefit of PDE5 inhibitors on urinary storage symptoms in men deserves further investigation.

suburothelium were mounted isometrically in organ baths filled with Krebs-HEPES (37 ° C; 95% O 2 /5% CO 2 ). Strips were incubated with 10 μ M pinacidil (K ATP opener) followed by 10 μ M glibenclamide (K ATP blocker). In another set of experiments, strips were incubated with 30 μ M NS-1619 (BK Ca opener) followed by 100 n M iberiotoxin (BK Ca blocker) or with 100 n M apamin (SK Ca blocker). RESULTSSCA occurred more frequently with larger amplitude and area under the curve in detrusor strips from NDO patients compared to control patients. The presence of urothelium/suburothelium did not significantly modify SCA in either patient population. Pinacidil markedly inhibited SCA of detrusor strips from control and NDO patients. This effect was reversed by glibenclamide. By contrast, NS-1619 followed by iberiotoxin did not elicit any significant changes in SCA from NDO patients, contrary to control patients. CONCLUSIONSK ATP and SK Ca channels regulate SCA of NDO patients' detrusor strips. By contrast, BK Ca channels are not involved in the regulation of detrusor SCA in NDO patients, whereas they regulate SCA in control patients. These results should be considered in the development of K + channels openers for the treatment of NDO. Moreover, SCA observed in vitro should be regarded as an in vitro modelling of human NDO.

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