Editorial Comment from Dr Michel to Expression and functional role of β₃‐adrenoceptors in the human ureter

Abstract

Editorial Comment from Dr Michel to Expression and functional role of b 3 -adrenoceptors in the human ureterb3-Adrenoceptorsare expressed in the urinary bladder and b3-adrenoceptor agonists have proven efficacious in the treatment of lower urinary tract symptoms.1,2 This subtype shows a more restricted expression pattern than b1-or b2-adrenoceptors, 3 which might contribute to an overall good tolerability of b3-adrenoceptor agonists. However, b3-adrenoceptors are found in a limited number of other tissues; for example, the retina and its blood vessels, 4,5 and this might give rise to additional indications for b3-adrenoceptor agonists. In this issue of the Journal, Matsumoto et al. report on the expression and function of b3-adrenoceptors in the human ureter.6 They propose that ureteral b3-adrenoceptors might be a target for medical stone expulsion therapy.The sympathetic nervous system contributes to the regulation of ureteral tone through both a1-and b-adrenoceptors, mediating smooth muscle contraction and relaxation, respectively. Distal ureter segments were reported to show a stronger b-adrenergic component, 7 which might be relevant as distal stones are anatomically more susceptible to medical expulsion therapy. The subtypes and function of b-adrenoceptors in the ureter of various animal species have previously been characterized. 8 They can reduce the ureteral pacemaker activity and cause smooth relaxation, but the relative role of subtypes varies markedly between species. A previous study has reported the presence of mRNA for all three b-adrenoceptor subtypes in the human ureter, and showed relaxation against passive tension by b 2-and b3-, but not by b1-adrenoceptor agonists; as a b2-selective antagonist showed only poor inhibition of relaxation, a major functional role of b3-adrenoceptors was implied. 9 The present study confirms the previously reported mRNA data, and expands them to the protein level using immunohistochemistry in both smooth muscle and urothelium; 6 in analogy to bladder findings, this raises the possibility that b3-adrenoceptor agonists in the ureter might also in part act indirectly on muscle tone by primarily affecting urothelial function. The present study also extends the previous functional findings by showing relaxation against KCl-and field stimulation-induced tone. A weakness of both studies is that many of the agonists being used have only limited subtype selectivity, and no thorough subtype identification based on highly selective antagonists was carried out. Nevertheless, the overall data point to the possibility that b 3-adrenoceptor agonists might be suitable for medical stone expulsion treatment, which would be very welcome in light of the limited efficacy of currently available medical treatment options. Although systemic administration of the partial b-adrenoceptoragonist oxprenolol 10 and endoluminal administration of isoprenaline 11 have shown promising results in clinical pilot studies, the validity of this concept needs to be verified in properly designed and power...