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The β -adrenoceptor Agonist Mirabegron Increases Human Atrial Force Through β -adrenoceptors: an Indirect Mechanism?

Overview
Journal Br J Pharmacol
Publisher Wiley
Specialty Pharmacology
Date 2017 Jun 3
PMID 28574581
Citations 26
Authors
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Abstract

Background And Purpose: Mirabegron has been classified as a β -adrenoceptor agonist approved for overactive bladder syndrome. We investigated possible cardiac effects of mirabegron in the absence or presence of β-adrenoceptor subtype antagonists. In view of its phenylethanolamine structure, we investigated whether mirabegron has indirect sympathomimetic activity by using neuronal uptake blockers.

Experimental Approach: Right atrial trabeculae, from non-failing hearts, were paced and contractile force measured at 37°C. Single concentrations of mirabegron were added in the absence or presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), β (L-748,337), β (CGP 20712A), β (ICI 118,551) -adrenoceptor antagonists, neuronal uptake inhibitors desipramine or phenoxybenzamine.

Key Results: Mirabegron significantly increased contractile force in human right atrium (1 μM, 7.6 ± 2.6%, n = 7; 10 μM, 10.2 ± 1.5%, n = 22 compared with (-)-isoprenaline P < 0.05). In the presence of IBMX, mirabegron (10 μM) caused a greater contraction. L-748,337 (100 nM) had no effect on the increase in contractile force caused by mirabegron (10 μM). In contrast, mirabegron (10 μM) reduced contractile force in the presence of CGP 20712A, which was not affected by L-748,337 (100 nM) or ICI 118,551 (50 nM). Mirabegron (10 μM) also reduced contractile force in the presence of desipramine or phenoxybenzamine.

Conclusions And Implications: Mirabegron increases human atrial force through β - but not β -adrenoceptors. Desipramine and phenoxybenzamine block neuronal uptake and conceivably prevent mirabegron from releasing noradrenaline. A non-specific cardiodepressant effect is not mediated through β (or β )-adrenoceptors, consistent with lack of β -adrenoceptor function on human atrial contractility.

Citing Articles

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PMID: 39204422 PMC: 11359404. DOI: 10.3390/pharmaceutics16081077.


Roles of β-adrenoceptor Subtypes and Therapeutics in Human Cardiovascular Disease: Heart Failure, Tachyarrhythmias and Other Cardiovascular Disorders.

Wong Y, Haqqani H, Molenaar P Handb Exp Pharmacol. 2024; 285:247-295.

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Adrenoceptors in the Lower Urinary Tract.

Hennenberg M, Michel M Handb Exp Pharmacol. 2023; 285:333-367.

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Treating and Managing Urinary Incontinence: Evolving and Potential Multicomponent Medical and Lifestyle Interventions.

Mohamed-Ahmed R, Taithongchai A, Da Silva A, Robinson D, Cardozo L Res Rep Urol. 2023; 15:193-203.

PMID: 37351339 PMC: 10284157. DOI: 10.2147/RRU.S387205.


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