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We compared the potency of a selective ureteral relaxant KUL-7211 (beta(2)/beta(3)-adrenoceptor agonist; (-)-2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenyloxy]acetic acid) with those of various spasmolytics on contractions in isolated canine ureteral preparations. Drug effects were evaluated on the tonic contraction induced by KCl (80 mM) and on spontaneous, 1x10(-5) M phenylephrine-, and 1x10(-6) M PGF(2alpha)-induced rhythmic contractions in isolated canine ureteral preparations using a functional experimental technique. The potencies (pD(2) value) of the following drugs were compared: KUL-7211, tamsulosin (an alpha(1A/1D)-adrenoceptor antagonist), prazosin (an alpha(1)-adrenoceptor antagonist), verapamil (a Ca(2+)-channel blocker), butylscopolamine (a nonselective muscarinic antagonist), and papaverine (a phosphodiesterase inhibitor). The rank order of relaxing potencies against KCl-induced tonic contraction was KUL-7211 (6.60)tamsulosin(5.90)verapamil(5.70)papaverine(4.88)prazosin (4.54). The rank order of potencies for reductions in spontaneous rhythmic contractions was KUL-7211 (6.80)verapamil(6.12)papaverine(5.05). Conversely, high concentrations of the two alpha-adrenoceptor antagonists (tamsulosin and prazosin) and of butylscopolamine enhanced the spontaneous contractions, although at low concentrations (up to 1x10(-6) M) they had no significant effects. For suppression of spasmogen-induced rhythmic contractions, the rank order of potencies was, against phenylephrine-induced contractions: KUL-7211 (6.95)tamsulosin(6.26)prazosin(5.68)verapamil(5.64)papaverine (5.03), and against PGF(2alpha)-induced contractions: KUL-7211 (7.05)verapamil(6.70)papaverine (5.27). Our results suggest that in dogs, the beta(2)/beta(3)-adrenoceptor agonist KUL-7211 is the most efficacious ureteral relaxant among the spasmolytics tested against various contractions. Possibly, KUL-7211 might be useful for promoting stone passage and relieving ureteral colic in urolithiasis patients.

Purpose: We evaluated the effects of the nonselective muscarinic receptor agonist carbachol (CCh) and its antagonist atropine on ureteral function in anesthetized dogs.Materials and Methods: Drug effects were evaluated on elevated pressure in a completely obstructed ureter and peristalsis in its partially obstructed fellow ureters as well as on intravesical isovolumetric pressure.Results: CCh (0.1 to 1.0 μg/kg intravenously) dose dependently decreased elevated pressure and peristalsis in completely and partially obstructed ureters, respectively, and increased intravesical isovolumetric pressure. On the other hand, atropine (0.1 to 1.0 mg/kg intravenously) had no significant effects on these 3 variables. Prior administration of atropine (1.0 mg/kg intravenously) completely inhibited the described CCh induced effects.Conclusions: Our results demonstrate that in anesthetized dogs cholinergic receptor stimulation has a suppressive effect on ureteral pressure and peristalsis in obstructed ureters, in c...

The purpose of present study was to characterize the functional muscarinic cholinoceptor (mAChR) subtypes in the isolated canine ureter. Carbachol (CCh), a non-selective mAChR agonist, concentration-dependently increased the frequency of the rhythmic contractions in isolated spiral ureteral preparations, the pD(2) value being 5.78+/-0.12. We then evaluated the effects of subtype-selective mAChR antagonists on the CCh-induced rhythmic contractions. The rank order of antagonistic potencies (apparent pA(2)) was 4-diphenylacetoxy- N-methylpiperidinemethiodide (4-DAMP; M3-subtype selective; 9.31+/-0.06)atropine (non-selective; 9.16+/-0.10)himbacine (M4-subtype selective; 7.32+/-0.18)pirenzepine (M1-subtype selective; 6.78+/-0.16)methoctramine (M2-subtype selective; 5.51+/-0.43). In sharp contrast, CCh concentration-dependently reduced the 80 mM KCl-induced contraction in longitudinal ureteral preparations, the pD(2) value being 4.83+/-0.10. On this CCh-induced ureteral relaxation, the rank order of antagonistic potencies (apparent pA(2)) was atropine (8.56+/-0.09)4-DAMP (7.63+/-0.21)himbacine (7.46+/-0.09)methoctramine (6.54+/-0.18)pirenzepine (6.33+/-0.22). The nitric-oxide-synthase inhibitor N(omega)-nitro-L-arginine (L-NOARG; 1 x 10(-4) M) had no effect on the CCh-induced ureteral relaxation. These data suggest that the CCh-induced rhythmic contraction in the spiral preparation was mediated via the M3-receptor, while the CCh-induced relaxation in the longitudinal preparation was probably mediated mainly via the M4-receptor.

Objectives To compare the potency and ureteral selectivity of the selective β2/β3-adrenoceptor agonist KUL-7211 with those of the nonselective β-adrenoceptor agonist isoproterenol, selective β2-adrenoceptor agonist terbutaline, and selective β3-adrenoceptor agonist CL-316243, we performed the study using an isolated porcine ureter and a porcine model of acute unilateral ureteral obstruction. Methods The effects of the drugs on the 80-mM KCl-induced contraction of the ureteral segments isolated from male pigs were evaluated using a functional experimental technique. Anesthetized male miniature pigs with complete obstruction of the left lower ureter were used to evaluate the effects of the cumulative intravenous drug administration on the elevated intraureteral pressure and mean blood pressure. Results The KCl-induced contractions in the isolated ureter were concentration-dependently attenuated by KUL-7211, isoproterenol, terbutaline, and CL-316243, with a rank order of potency of 6.26, 6.98, 5.41, and 5.41, respectively. In the anesthetized pigs, all 4 drugs reduced the unilateral ureteral obstruction-induced elevated intraureteral pressure in a dose-dependent manner, with KUL-7211 reducing it with a lower hypotensive effect than either isoproterenol or terbutaline. The ureteral selectivity (defined as the ratio of the effective dose to decrease the mean blood pressure by 25% to the effective dose to decrease the intraureteral pressure by 50%) of KUL-7211 (1.5) was significantly greater than that of isoproterenol (0.04) or terbutaline (0.43). Conclusions The present results have demonstrated that in pigs, KUL-7211 is a potent ureteral relaxant with a relatively small hypotensive effect. A selective β2/β3-adrenoceptor agonist, such as KUL-7211, warrants additional investigation as a potentially useful drug for the promotion of stone passage in patients with urolithiasis.