An Exploratory Study in Healthy Male Subjects of the Mechanism of Mirabegron‐Induced Cardiovascular Effects

Abstract

To explore the role of β -adrenoceptors (ARs) in the heart rate response to the selective β -adrenoceptor agonist mirabegron, 12 young male volunteers received single oral doses of the nonselective β -AR antagonist propranolol (160 mg), the selective β -AR antagonist bisoprolol (10 mg), or placebo on days 1 and 5 of each period in a 3-period crossover study. On day 5, dosing was followed by a supratherapeutic dose of mirabegron (200 mg). Vital signs, impedance cardiography, and plasma renin activity were collected. Mirabegron increased heart rate and systolic blood pressure and reduced stroke volume, whereas cardiac output and diastolic blood pressure were unaffected. Mirabegron-induced changes were attenuated by propranolol and bisoprolol. The data indicate that mirabegron has a positive chronotropic effect at supratherapeutic concentrations, which is at least partly mediated by stimulation of β -AR.

Mirabegron: potential off target effects and uses beyond the bladder

“…In healthy volunteers, high doses (100–200 mg) of mirabegron increased heart rate and blood pressure, whereas lower therapeutic doses (50 mg) in OAB patients resulted in minor changes in pulse rate (1 beat per minute) and diastolic/systolic blood pressure (1 mm Hg or less) (Chapple et al, ; Nitti et al, ). A subsequent recent clinical study (van Gelderen et al, ) in healthy volunteers showed that a supra‐therapeutic dose of mirabegron (200 mg) increased heart rate and systolic (but not diastolic) blood pressure via activation of β 1 ‐adrenoceptors, as effects were attenuated by co‐administration of either propranolol or bisoprolol.…”

Cardiac β3‐adrenoceptors—A role in human pathophysiology?

“…Supratherapeutic doses of mirabegron (100-200 mg) increased heart rate in a Phase II dose-ranging study (Chapple et al, 2013). In a follow-up study in young, healthy volunteers treated with the 200 mg dose, this increase was confirmed, and was markedly attenuated by co-administration of propranolol or bisoprolol (van Gelderen et al, 2017), suggesting that the β 1adrenoceptor was largely involved in this response. Clinical studies with mirabegron, when used for the treatment of patients with overactive bladder syndrome, have detected only small if any increases in heart rate (Michel & Gravas, 2016;Rosa et al, 2018).…”

“…Clinical studies with mirabegron, when used for the treatment of patients with overactive bladder syndrome, have detected only small if any increases in heart rate (Michel & Gravas, 2016;Rosa et al, 2018). In the light of the above findings in healthy volunteers (van Gelderen et al, 2017) and those in isolated human atrium (Mo et al, 2017), these responses to mirabegron can most likely be explained by peripheral vasodilation and/or indirect sympathomimetic effects. However, neither of these hypotheses has been proven in humans.…”

Cardiovascular effects of antimuscarinic agents and beta3-adrenergic receptor agonist for the treatment of overactive bladder

“…Although pharmacological mechanisms of mirabegron on inducing CV effects are not fully understood, an experiment study conducted by Van Gelderen et al [47] in human healthy volunteers has shown interesting results. In this study, the administration of a supratherapeutic dose (200 mg) of mirabegron in combination with the β1 selective antagonist bisoprolol or the β1/ β2 antagonist propanolol showed in both cases a reduction in mirabegron positive chronotropic and hypertensive effects suggesting that these are at least partly mediated by β1 receptor stimulation.…”