Editorial: β3‐adrenoceptor agonists inhibit calcium oscillations in bladder detrusor

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.