The β3‐adrenoceptor (β3‐AR) agonist mirabegron has now been used clinically for the treatment for overactive bladder (OAB) for 5 years, but it is still not clear either exactly where the β3‐ARs are located within the bladder wall or entirely how they work. β3‐AR agonists can reduce detrusor contractions after cholinergic stimulation, but the concentrations of mirabegron required for this effect suggest that this is unlikely to be the main therapeutic route, which may instead involve an indirect pathway or a combination of pathways.
In this issue of BJUI, Griffin et al. 1 show that β3‐AR agonists can reduce the rise in calcium and calcium waves observed after muscarinic receptor activation with carbachol in murine detrusor smooth muscle. They convincingly demonstrate that this effect is mediated by β3‐AR rather than by β1‐AR or β2‐AR and is not mediated by an effect on L‐type calcium channels or depletion of calcium stores; however, although they use BRL37344 and CL316,243, which have a higher potency in rodents than mirabegron, the concentrations of these agents needed are in the micromolar range, significantly higher than the values of ~100 nM measured in plasma following therapeutic dosing with mirabegron 2. It will be interesting to see when these experiments are repeated with, these effects on calcium are also seen in the therapeutic dosing range.
Currently, the only effects of mirabegron reported in the therapeutic dosing range are a reduction in detrusor contractions when elicited by field stimulation and a reduction in acetylcholine release from detrusor strips 3, 4. The similarly of the concentrations required for these two effects have led to the suggestion that the reduction in contractions may be mediated by the reduction in acetylcholine release; however, there is still disagreement as to whether β3‐ARs are located in the cholinergic nerve terminals or not, as different groups have obtained different patterns of β3‐adrenoreceptor staining, even when using the same antibodies 4–6. It is therefore still unclear if this involves a direct inhibition of acetylcholine release or not, although a predominantly neural source of acetylcholine is indicated by sensitivity to the sodium channel blocker, tetrodotoxin 3.
There is evidence that the reduction may be at least partially mediated via adenosine, such that increased adenosine formed post‐junctionally from breakdown of cAMP following β3‐AR stimulation, acts as a retrograde transmitter to inhibit acetylcholine release by acting at pre‐junctional A1 receptors 4. In support of this, Silva et al. 4 showed that A1 antagonists can reverse the increase in voiding seen with isoprenaline in an anaesthetized rat cystoscopy model.
The reduction in calcium rise reported by Griffin et al. 1 also suggests a post‐junctional site of action and the likely possibility that multiple pathways are activated following the binding of the β3‐AR agonists to post‐junctional receptors. A multiple pronged mechanism may be one of the reasons why mirabegron is successful at reducing the symptoms of OAB whilst sparing normal voiding.
The potency of β3‐AR agonists shows differences depending on the method of stimulation of the muscle, with higher potency seen for inhibition of contraction induced by field stimulation than carbachol stimulation, for example 1, 3, 4. This may reflect differences in the combinations of pathways and receptors activated, with carbachol stimulating only the muscarinic receptors themselves, but field stimulation activating more widely. It would therefore be interesting to see whether the potency of mirabegron to affect calcium release in human tissue is higher when field stimulation is used rather than carbachol, and hence help to evaluate if this pathway is involved in the mechanism of action of mirabegron in the clinic.
- 1 Griffin CS, Bradley E, Hollywood MA, McHale NG, Thornbury KD, Sergeant GP. B3‐adrenoceptor agonists inhibit carbachol‐evoked Ca2+ oscillations in murine detrussor myocytes. BJU Int 2018; 121: 959–70
- 2 Krauwinkel W, van Dijk J, Schaddelee M et al. Pharmacokinetic properties of mirabegron, a beta(3)‐adrenoceptor agonist: results from two phase I, randomized, multiple‐dose studies in healthy young and elderly men and women. Clin Ther 2012; 34: 2144–60
- 3 D’Agostino G, Condino AM, Calvi P. Involvement of beta(3)‐adrenoceptors in the inhibitory control of cholinergic activity in human bladder: direct evidence by H‐3‐acetylcholine release experiments in the isolated detrusor. Eur J Pharmacol 2015; 758: 115–22
- 4 Silva I, Costa AF, Moreira S et al. Inhibition of cholinergic neurotransmission by beta(3)‐adrenoceptors depends on adenosine release and A(1)‐receptor activation in human and rat urinary. Am J Physiol‐Renal Physiol 2017; 313: F388–403
- 5 Coelho A, Antunes‐Lopes T, Gillespie J, Cruz F. Beta‐3 adrenergic receptor is expressed in acetylcholine‐containing nerve fibers of the human urinary bladder: an immunohistochemical study. Neurourol Urodyn 2017; 36: 1972–80
- 6 Limberg BJ, Andersson KE, Kullmann FA, Burmer G, de Groat WC, Rosenbaum JS. beta‐Adrenergic receptor subtype expression in myocyte and non‐myocyte cells in human female bladder. Cell Tissue Res 2010; 342: 295–306