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Keywords: hydrogen sulfide; urothelium; urothelium-derived relaxing factor; bladder; 3 adrenoceptor EN hydrogen sulfide urothelium urothelium-derived relaxing factor bladder 3 adrenoceptor N.PAG N.PAG 13 08/29/22 20220801 NES 220801 1. 3 Relaxant Effect in Human Bladder Involves Cystathionine -Lyase-Derived Urothelial Hydrogen Sulfide Since it is known that (i) SB 3 sb AR is expressed in the human detrusor and urothelium [[31]], and (ii) SB 3 sb AR stimulation relaxes the human corpus cavernosum through H SB 2 sb S release [[33]], here, we have investigated the contribution of the urothelium and the possible involvement of the H SB 2 sb S pathway in SB 3 sb -induced relaxation in the human bladder. Moreover, sodium hydrogen sulfide and L-cysteine (exogenous and endogenous sources of H SB 2 sb S, respectively) relax in a concentration-dependent manner human bladder strips precontracted with carbachol, indicating a relevant role for H SB 2 sb S in bladder homeostasis [[21]]. [Extracted from the article]

It is now well established that the urothelium does not act as a passive barrier but contributes to bladder homeostasis by releasing several signaling molecules in response to physiological and chemical stimuli. Here, we investigated the potential contribution of the hydrogen sulfide (H2S) pathway in regulating human urothelium function in β3 adrenoceptor-mediated relaxation. The relaxant effect of BRL 37344 (0.1–300 µM), a selective β3 adrenoceptor agonist, was evaluated in isolated human bladder strips in the presence or absence of the urothelium. The relaxant effect of BRL 37344 was significantly reduced by urothelium removal. The inhibition of cystathionine-γ-lyase (CSE), but not cystathionine-β-synthase (CBS), significantly reduced the BRL 37344 relaxing effect to the same extent as that given by urothelium removal, suggesting a role for CSE-derived H2S. β3 adrenoceptor stimulation in the human urothelium or in T24 urothelial cells markedly increased H2S and cAMP levels that were reverted by a blockade of CSE and β3 adrenoceptor antagonism. These findings demonstrate a key role for urothelium CSE-derived H2S in the β3 effect on the human bladder through the modulation of cAMP levels. Therefore, the study establishes the relevance of urothelial β3 adrenoceptors in the regulation of bladder tone, supporting the use of β3 agonists in patients affected by an overactive bladder.