Signalling pathways involved in sildenafil-induced relaxation of human bladder dome smooth muscle

Abstract

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 μM) 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 μM. This effect was not modified by NO donors, S-nitroso-N-acetylpenicillamine (10 μM) or sodium nitroprusside (300 nM), but was significantly inhibited by inhibition of guanylate cyclase (with ODQ, 10 μM) or adenylyl cyclase (with MDL-12,330A, 10 μM), by the ATP-sensitive potassium channel inhibitor, glibenclamide (10 μM), 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. © 2010 The British Pharmacological Society.