The β3 -adrenoceptor agonist mirabegron increases human atrial force through β1 -adrenoceptors: an indirect mechanism?

Abstract

BACKGROUND AND PURPOSE:

Mirabegron has been classified as a β3 -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), β3 (L-748,337), β1 (CGP 20712A), β2 (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 β1 - but not β3 -adrenoceptors. Desipramine and phenoxybenzamine block neuronal uptake and conceivably prevent mirabegron from releasing noradrenaline. A non-specific cardiodepressant effect is not mediated through β3 (or β2 )-adrenoceptors, consistent with lack of β3 -adrenoceptor function on human atrial contractility.

• Authors: Weilan Mo, Martin C Michel, Xiang Wen Lee, Alberto J Kaumann, Peter Molenaar
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 174 Issue 16 Pg. 2706-2715 (Aug 2017) ISSN: 1476-5381 [Electronic] England
• PMID: 28574581 (Publication Type: Journal Article)
• Copyright: © 2017 The British Pharmacological Society.

Chemical References

• Acetanilides
• Adrenergic beta-Agonists
• Adrenergic beta-Antagonists
• Imidazoles
• Propanolamines
• Receptors, Adrenergic, beta
• Thiazoles
• ICI 118551
• CGP 20712A
• mirabegron
• 1-Methyl-3-isobutylxanthine

Topics

• 1-Methyl-3-isobutylxanthine (pharmacology)
• Acetanilides (pharmacology)
• Adrenergic beta-Agonists (pharmacology)
• Adrenergic beta-Antagonists (pharmacology)
• Aged
• Atrial Function (drug effects)
• Female
• Heart Atria (drug effects)
• Humans
• Imidazoles (pharmacology)
• In Vitro Techniques
• Male
• Middle Aged
• Myocardial Contraction (drug effects)
• Propanolamines (pharmacology)
• Receptors, Adrenergic, beta (physiology)
• Thiazoles (pharmacology)