The goal of medical expulsive therapy is to induce relaxation of the ureteral tube to allow stone passage and reduce colic, which is an excruciating pain commonly experienced by urinary stone patients. β-adrenoceptors, particularly the β3 subtype, have been shown to relax smooth muscle cells of the bladder [1] and urethra [2]. We hypothesised that a similar pharmacological profile would be observed in the ureter. The aim of this study is to investigate whether there is a role for β-adrenoceptors in the modulation of isolated distal ureteral contractility, and to identify the receptor subtype mediating this effect.

Paired tissue strips isolated from the porcine distal ureter were subjected to 5-HT (100µM). The 5-HT-induced contractile responses were allowed to stabilise to generate a consistent pattern. Subsequently, these responses were examined in the absence (vehicle control) and presence of increasing concentrations of isoprenaline (general β-adrenoceptor antagonist, 100nM-1mM), mirabegron (β3-adrenoceptor agonist, 100nM-1mM), CGP 12177A (β3-adrenoceptor agonist, 10nM-100µM) or salbutamol (β2-adrenoceptor agonist, 100nM-1mM).

When subjected to 5-HT (100µM), the porcine ureteral tissues developed bursts of phasic contractions which were measured and expressed as frequency, amplitude, and area under the curve (AUC). Isoprenaline, at concentrations 1µM and higher, produced concentration-dependent ureteral relaxations in the contractile responses expressed as frequency (Figure 1A), amplitude (Figure 1B) and AUC (Figure 1C). Neither mirabegron, CGP 12177A nor salbutamol produced this relaxatory response. Mirabegron, at 100µM and above, reduced only the amplitude of the 5-HT-induced contractile response (p<0.05, mirabegron vs vehicle control; 100µM: 89.4±1.4 vs 95.3±0.6%, 1mM: 77.4±1.1% vs 93.4±0.2%) while CGP 12177A, at 10µM and above, reduced the frequency of the phasic contractions (p<0.05, CGP 12177A vs vehicle control; 10µM: 56.6±3.3% vs 77.8±2.6%, 100µM: 28.3±5.4% vs 68.7±0.6%). Salbutumol was capable of significantly reducing the frequency and amplitude of the phasic contractions at 1mM (p<0.05, salbutamol vs vehicle control; frequency: 51.6±9.3 vs 70.8±1.6 %, amplitude: 81.9±0.4 vs 94.2±1.6%).

Our results suggest that β-adrenoceptors have a functional role in inducing a relaxation in the porcine distal ureter by reducing both the frequency and amplitude of phasic contractions. The inability of mirabegron, CGP 12177A or salbutamol to reproduce this relaxation at concentrations that they effectively bind to β3 or β2-adrenoceptors suggest that these are not the subtypes mediating the isoprenaline-induced ureteral relaxation [3].

The relaxation of the ureteral tube is modulated by β-adrenoceptors via an unknown subtype that is not β2 or β3. Further investigations are required, but these findings suggest a potential for effective use of β-adrenoceptor agonists as an agent for medical expulsive therapy.

Fujimura T, Tamura K, Tsutsumi T, et al. Expression and possible functional role of the beta3-adrenoceptor in human and rat detrusor muscle. J Urol. Feb 1999;161(2):680-5.
Alexandre EC, Kiguti LR, Calmasini FB, et al. Mirabegron relaxes urethral smooth muscle by a dual mechanism involving beta3 -adrenoceptor activation and alpha1 -adrenoceptor blockade. Br J Pharmacol. Feb 2016;173(3):415-28. doi:10.1111/bph.13367
Baker JG. The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors. Br J Pharmacol. Feb 2005;144(3):317-22. doi:10.1038/sj.bjp.0706048