title: Involvement of β3-adrenoceptors in the inhibitory control of cholinergic activity in human bladder: Direct evidence by [(3)H]-acetylcholine release experiments in the isolated detrusor.
abstract: Bladder overactivity (OAB) is a multifactorial bladder disorder that requires therapeutics superior to the current pharmacological treatment with muscarinic antagonists. β3-adrenoceptor (β3-ADR) agonists represent a novel promising approach that differently addresses the parasympathetic pathway, but the clinical efficacy of these drugs has not been fully elucidated to date. Therefore, we aimed to study the pharmacological mechanisms activated by β3-ADR agonists at muscular and neural sites in the isolated human bladder. Detrusor smooth muscle strips obtained from male patients undergoing total cystectomy were labelled with tritiated choline and stimulated with electrical field stimulation (EFS). EFS produced smooth muscle contraction and simultaneous acetylcholine ([(3)H]-ACh) release, which mostly reflects the neural origin of acetylcholine. Isoprenaline (INA), BRL37344 and mirabegron inhibited the EFS-evoked contraction and [(3)H]-ACh release in a concentration-dependent manner, yielding concentration-response curves (CRCs) that were shifted to the right by the selective β3-ADR antagonists L-748,337 and SR59230A. Based on the agonist potency estimates (pEC50) and apparent affinities (pKb) of antagonists evaluated from the CRCs of agonists, our data confirm the occurrence of β3-ADRs at muscle sites. Moreover, our data are consistent with the presence of inhibitory β3-ADRs that are functionally expressed at the neural site. Taken together, these findings elucidate the mechanisms activated by β3-ADR agonists because neural β3-ADRs participate in the inhibition of detrusor motor drive by reducing the amount of acetylcholine involved in the cholinergic pathway.
authors: Department of Drug Science, Experimental Pharmacology Unit, University of Pavia, Italy. Electronic address: dagg@unipv.it.
authors: Gianluigi
authors: G
authors: D' Agostino
authors: Department of Drug Science, Experimental Pharmacology Unit, University of Pavia, Italy.
authors: Anna
authors: A
authors: Maria Condino
authors: Urological Unit, Santa Rita Clinic Hospital, Vercelli, Italy.
authors: Paolo
authors: P
authors: Calvi
mesh_terms: D000083:Acetanilides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism*; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology*; D000627:Aminophenols / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004983:Ethanolamines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D011412:Propanolamines / Q000494:pharmacology; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology*
chemical_list: C097869:3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate; D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D000627:Aminophenols; D004983:Ethanolamines; C120576:L 748,337; D011412:Propanolamines; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides; D013844:Thiazoles; C057368:BRL 37344; D007545:Isoproterenol; C520025:mirabegron; D000109:Acetylcholine
keywords: Acetylcholine release; Human detrusor; Mirabegron; Overactive bladder; Pre-junctional receptors; β(3)-Adrenoreceptors