Inhibition of prejunctional parasympathetic pathways by β 3 -adrenoceptor agonists in the isolated pig detrusor: comparison with human detrusor studies

LMR Unit ,University of Pavia ,Pavia ,Italy
D’Agostino, Gianluigi;
Department of Obstetrics and Gynaecology ,Vita-Salute San Raffaele University ,IRCCS San Raffaele Scientific Institute ,Milan ,Italy
Salvatore, Stefano;
Cellini Clinic ,Humanitas Group ,Torino ,Italy
Calvi, Paolo;
Department of Drug Sciences ,University of Pavia ,Pavia ,Italy
Condino, Anna Maria

Adrenergic receptors of the β 3 -subtype (β 3 -ADRs) seem to represent a new target for a more effective pharmacological treatment of overactive bladder (OAB), a wide spread urinary disorder. A promising opportunity for OAB therapy might rely on the development of selective β 3 -ADR agonists, but an appropriate preclinical screening, as well as investigation of their pharmacological mechanism(s), is limited by poor availability of human bladder samples and of translational animal models. In this study, we used the porcine urinary bladder as experimental tool to ascertain the functions of β 3 -ADRs in the control the parasympathetic motor drive. Tritiated acetylcholine ([ 3 H]-ACh), mainly originated from neural stores, was released by electrical field stimulation (EFS) in epithelium-deprived detrusor strips from pigs bred without estrogens. EFS produced simultaneously [ 3 H]-ACh release and smooth muscle contraction allowing to asses neural (pre-junctional) and myogenic (postjunctional) effects in the same experiment. Isoprenaline and mirabegron produced on the EFS-evoked effects a concentration-dependent inhibition antagonized by L-748,337, a high selective β 3 -ADR antagonist. The analysis of the resultant pharmacodynamic parameters supports the notion that in pig detrusors, as well as in previously described human detrusors, the activation of inhibitory β 3 -ADRs can modulate neural parasympathetic pathways. In such inhibitory control, the involvement of membrane K + channels, mainly of the SK type, seems to play a pivotal role similarly to what previously described in humans. Therefore, the isolated porcine detrusor can provide a suitable experimental tool to study the mechanisms underlying the clinical efficacy of selective β 3 -ADR compounds for human use.


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