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

Abstract

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. 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 microM) were generated in the presence of various inhibitors on carbachol-induced pre-contraction. Sildenafil relaxed carbachol-pre-contracted human detrusor strips, starting at 3 microM. This effect was not modified by NO donors, S-nitroso-N-acetylpenicillamine (10 microM) or sodium nitroprusside (300 nM), but was significantly inhibited by inhibition of guanylate cyclase (with ODQ, 10 microM) or adenylyl cyclase (with MDL-12,330A, 10 microM), by the ATP-sensitive potassium channel inhibitor, glibenclamide (10 microM), or inhibition of the large (with iberiotoxin, 30 nM) or small (with apamin, 100 nM) conductance calcium-activated potassium channels. 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.