Nitrergic inhibition of sympathetic arteriolar constrictions in the female rodent urethra

• Published in: The Journal of physiology 2024-05, Vol.602 (10), p.2199-2226
• Main Authors: Hashitani, Hikaru, Mitsui, Retsu, Hirai, Yuuna, Tanaka, Hidekazu, Miwa‐Nishimura, Kyoko
• Format: Article
• Language: English
• Subjects: Acetylcholine; Animals; Arterioles; Arterioles - drug effects; Arterioles - metabolism; Arterioles - physiology; Atropine; Bladder; Calcitonin gene-related peptide; Calcium signalling; CGRP; Endothelial cells; Endothelium; Energy consumption; Female; Immunohistochemistry; Innervation; Ischemia; Mice; Mice, Inbred C57BL; Muscle contraction; nitric oxide; Norepinephrine; parasympathetic nerve; Parasympathetic nervous system; Parvalbumin; Phenylephrine; Prazosin; Rats; Rats, Sprague-Dawley; Sensory neurons; Smooth muscle; sympathetic nerve; Sympathetic nerves; Sympathetic Nervous System - drug effects; Sympathetic Nervous System - physiology; Synaptic transmission; Tyrosine 3-monooxygenase; Urethra; Urethra - drug effects; Urethra - innervation; Urethra - physiology; Vasoconstriction - drug effects; Vesicular acetylcholine transporter
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP285583

During the urine storage phase, tonically contracting urethral musculature would have a higher energy consumption than bladder muscle that develops phasic contractions. However, ischaemic dysfunction is less prevalent in the urethra than in the bladder, suggesting that urethral vasculature has intrinsic properties ensuring an adequate blood supply. Diameter changes in rat or mouse urethral arterioles were measured using a video‐tracking system. Intercellular Ca2+ dynamics in arteriolar smooth muscle (SMCs) and endothelial cells were visualised using NG2‐ and parvalbumin‐GCaMP6 mice, respectively. Fluorescence immunohistochemistry was used to visualise the perivascular innervation. In rat urethral arterioles, sympathetic vasoconstrictions were predominantly suppressed by α,β‐methylene ATP (10 μM) but not prazosin (1 μM). Tadalafil (100 nM), a PDE5 inhibitor, diminished the vasoconstrictions in a manner reversed by N‐ω‐propyl‐l‐arginine hydrochloride (l‐NPA, 1 μM), a neuronal NO synthesis (nNOS) inhibitor. Vesicular acetylcholine transporter immunoreactive perivascular nerve fibres co‐expressing nNOS were intertwined with tyrosine hydroxylase immunoreactive sympathetic nerve fibres. In phenylephrine (1 μM) pre‐constricted rat or mouse urethral arterioles, nerve‐evoked vasodilatations or transient SMC Ca2+ reductions were largely diminished by l‐nitroarginine (l‐NA, 10 μM), a broad‐spectrum NOS inhibitor, but not by l‐NPA. The CGRP receptor antagonist BIBN‐4096 (1 μM) shortened the vasodilatory responses, while atropine (1 μM) abolished the l‐NA‐resistant transient vasodilatory responses. Nerve‐evoked endothelial Ca2+ transients were abolished by atropine plus guanethidine (10 μM), indicating its neurotransmitter origin and absence of non‐adrenergic non‐cholinergic endothelial NO release. In urethral arterioles, NO released from parasympathetic nerves counteracts sympathetic vasoconstrictions pre‐ and post‐synaptically to restrict arteriolar contractility. Key points Despite a higher energy consumption of the urethral musculature than the bladder detrusor muscle, ischaemic dysfunction of the urethra is less prevalent than that of the bladder. In the urethral arterioles, sympathetic vasoconstrictions are predominately mediated by ATP, not noradrenaline. NO released from parasympathetic nerves counteracts sympathetic vasoconstrictions by its pre‐synaptic inhibition of sympathetic transmission as well as post‐synaptic arteriolar smooth muscle relaxation. Acetylc