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

Autor: Christian Steinhäuser, Hidekazu Tanaka, Stefan Passlick, Hikaru Hashitani, Retsu Mitsui, Kenji F. Tanaka, Mitsuhiro Oishi, Ronald Jabs
Rok vydání: 2021
Předmět:
Zdroj: British Journal of Pharmacology. 178:1073-1094
ISSN: 1476-5381
0007-1188
Popis: BACKGROUND AND PURPOSE While 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 APPROACH Diameter 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 RESULTS In 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 IMPLICATIONS Both 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.
Databáze: OpenAIRE
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