Do β₃-adrenoceptor agonists cause urinary bladder smooth muscle relaxation by inhibiting acetylcholine release?

Mirabegron: potential off target effects and uses beyond the bladder

“…(), the authors showed that β 3 ‐adrenoceptor activation (albeit mainly using isoprenaline) increases adenosine release from detrusor muscle via equilibrative nucleoside transporters, leading to retrograde activation of prejunctional adenosine A 1 receptors, which inhibit acetylcholine release from cholinergic nerves in both rat and human urinary bladders. The potential significance and relevance of these results has recently been reviewed (Okeke et al, ).…”

β3‐adrenoceptor agonists inhibit carbachol‐evoked Ca2+ oscillations in murine detrusor myocytes

“…Determination of the site and mechanism of action of β3‐AR agonists, such as mirabegron, for treatment of OAB is currently the subject of intense debate within the field . Several cell types within the bladder have been reported either to express β3‐ARs or be responsive to β3‐AR agonists, including detrusor smooth muscle, urothelium, afferent nerves, interstitial cells, blood vessels and the major pelvic ganglion .…”

“…Indeed, a recent editorial by Okeke et al. described how various investigators, even within the same institute, using similar approaches and antibodies have obtained conflicting results, with no obvious explanation for the divergent findings. These authors concluded that additional studies are required to determine the functional responses of cells involved in detrusor tone to application of β3‐AR agonists.…”

“…b3-adrenoceptor (b3-AR) agonists, such as mirabegron, represent a novel class of drugs to treat overactive bladder (OAB) syndrome [1,2]; however, there is little agreement on either the site of or mechanism of action for these drugs. Indeed, a recent editorial by Okeke et al [3] described how various investigators, even within the same institute, using similar approaches and antibodies have obtained conflicting results, with no obvious explanation for the divergent findings. These authors concluded that additional studies are required to determine the functional responses of cells involved in detrusor tone to application of b3-AR agonists.…”

β3 Adrenoceptor‐induced cholinergic inhibition in human and rat urinary bladders involves the exchange protein directly activated by cyclic AMP 1 favoring adenosine release

“…Selective β 3 -adrenoceptor agonists, such as mirabegron, are increasingly prescribed as alternatives to anti-muscarinic drugs in the treatment of overactive bladder (OAB) syndrome (Angulo, Khullar, Nitti, & Siddiqui, 2013;Marcelissen, Rashid, Antunes-Lopes, Delongchamps, & Geavlete, 2019). Regardless of their clinical success and that they are associated with fewer side effects compared to anti-muscarinic drugs, controversy exists regarding the dominant localization of β 3 -adrenoceptors on detrusor smooth muscle fibres and the molecular mechanism(s) underlying their overall mechanism (Andersson, 2017;Igawa & Aizawa, 2017;Igawa, Aizawa, & Michel, 2019;Okeke, Gravas, & Michel, 2017).…”