Nitric oxide‐mediated signal transmission in bladder vasculature underlies the therapeutic actions of PDE5 inhibitors in the rat

Abstract

Background and PurposeWhile the bladder vasculature is considered as a target of PDE5 inhibitors to improve bladder storage dysfunctions, its characteristics are largely unknown. Thus, the functional and morphological properties of arteries/arterioles of the bladder focusing on the NO‐mediated signal transmission were explored.Experimental ApproachDiameter changes in rat bladder arteries/arterioles were measured using a video‐tracking system. Intercellular Ca2+ dynamics in pericytes or smooth muscle cells (SMCs) of suburothelial arterioles were visualised using transgenic mice expressing GCaMP6 under control of the NG2‐ or parvalbumin‐promoter. The perivascular innervation was investigated using fluorescence immunohistochemistry.Key ResultsIn rat suburothelial arterioles and vesical arteries, tadalafil (100 nM) attenuated nerve‐evoked sympathetic vasoconstrictions. In both vascular segments, tadalafil‐induced inhibition of sympathetic vasoconstriction was prevented by N ω‐propyl‐l‐arginine hydrochloride (l‐NPA, 1 μM), an nNOS inhibitor or N ω‐nitro‐l‐arginine (l‐NA, 100 μM). Both vascular segments were densely innervated with nNOS‐positive nitrergic nerves in close apposition to tyrosine hydroxylase‐immunoreactive sympathetic nerves. In pericyte‐covered pre‐capillary arterioles of the mouse bladder where sympathetic nerves were absent, nerve stimulation evoked transient reductions in pericyte Ca2+ levels that were shortened by l‐NPA and abolished by l‐NA. In SMC‐containing arterioles, tadalafil (10 nM) caused a l‐NPA‐sensitive suppression of sympathetic Ca2+ transients. In mice, nitrergic perivascular nerves were distributed in the arterioles and the pre‐capillary arterioles.Conclusion and ImplicationsBoth nitrergic nerve and nerve‐evoked endothelial NO release appear to be involved in vasodilatory signal transmission in bladder vasculature. The NO‐mediated signal transmission is a potential target for PDE5 inhibitor therapy in bladder dysfunctions.