PubMed | University of Pavia and Santa Rita Clinic Hospital
Type: | Journal: European journal of pharmacology | Year: 2015
Bladder overactivity (OAB) is a multifactorial bladder disorder that requires therapeutics superior to the current pharmacological treatment with muscarinic antagonists. 3-adrenoceptor (3-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 3-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 3-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 3-ADRs at muscle sites. Moreover, our data are consistent with the presence of inhibitory 3-ADRs that are functionally expressed at the neural site. Taken together, these findings elucidate the mechanisms activated by 3-ADR agonists because neural 3-ADRs participate in the inhibition of detrusor motor drive by reducing the amount of acetylcholine involved in the cholinergic pathway.