Mirabegron attenuates porcine ureteral contractility via α1-adrenoceptor antagonism

Abstract

The β3-agonist mirabegron is thought to induce relaxation of the detrusor muscle, contributing to the improvement of overactive bladder symptoms. There has been recent interest in purposing mirabegron as a medical expulsive therapy drug to improve the passage of smaller kidney stones by relaxing the ureteral smooth muscles. The aim of this study was to determine the effects of mirabegron on the activity of the ureter. Additionally, we investigated the receptor and mechanisms through which mirabegron exerts these effects. In vitro agonist-induced responses of isolated porcine distal ureteral tissues were measured in the absence and presence of mirabegron in organ bath experiments. The responses were expressed as frequency, area under the curve and maximum amplitude. Mirabegron at concentrations of 100 nM and lower failed to suppress phenylephrine- or 5-HT-induced contractions in the porcine ureteral strip. Mirabegron at 1 μM and 10 μM produced a rightward shift of phenylephrine concentration–response curves in these tissues. This effect of mirabegron (10 μM) was not present in 5-HT concentration–response curves. The mirabegron effect on phenylephrine-induced contractions was also not abolished by β-adrenoceptor antagonist SR 59230A (10 μM), β-adrenoceptor antagonist propranolol (10 μM), α2-adrenoceptor antagonist yohimbine (30 nM), and nitric oxide synthase inhibitor l-NNA (10 μM). The present results show that mirabegron suppresses ureteral contractile responses in the porcine ureter via α1-adrenoceptor antagonism, since their effects were not present when the tissues were contracted with 5-HT. Furthermore, the inhibitory effects by mirabegron were not affected by β3-adrenoceptor antagonists.

Inhibition of PDE‐4 isoenzyme attenuates frequency and overall contractility of agonist‐evoked ureteral phasic contractions

“…To investigate potential relaxatory effects of PDE inhibitors, such as rolipram (PDE‐4), piclamilast (PDE‐4), roflumilast (PDE‐4), sildenafil (PDE‐5), and tadalafil (PDE‐5), on contractile activity of ureteral smooth muscle, phasic pre‐contractions were induced by 5‐HT (100 μM) in paired tissue strips. This pre‐contractile agent provides a stable production of phasic activity as has been reported in a previous study within our laboratory 30 . Upon generation of a consistent pattern of phasic contractile activity (approximately 10 min), one PDE inhibitor was cumulatively added to one tissue strip (0.1 nM–10 μM for all, except for piclamilast where 0.01 nM–1 μM was used), while the other strip acted as a vehicle and time control.…”

“…This pre-contractile agent provides a stable production of phasic activity as has been reported in a previous study within our laboratory. 30 Upon generation of a consistent pattern of phasic contractile activity (approximately 10 min), one PDE inhibitor was cumulatively added to one tissue strip (0.1 nM-10 μM for all, except for piclamilast where 0.01 nM-1 μM was used), while the other strip acted as a vehicle and time control. One tissue strip was only ever exposed to one PDE inhibitor.…”