cl-316243 and Ureteral-Obstruction

To compare the potency and ureteral selectivity of the selective β(2)/β(3)-adrenoceptor agonist KUL-7211 with those of the nonselective β-adrenoceptor agonist isoproterenol, selective β(2)-adrenoceptor agonist terbutaline, and selective β(3)-adrenoceptor agonist CL-316243, we performed the study using an isolated porcine ureter and a porcine model of acute unilateral ureteral obstruction.. 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.. 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).. The present results have demonstrated that in pigs, KUL-7211 is a potent ureteral relaxant with a relatively small hypotensive effect. A selective β(2)/β(3)-adrenoceptor agonist, such as KUL-7211, warrants additional investigation as a potentially useful drug for the promotion of stone passage in patients with urolithiasis.

Topics: Acetates; Acute Disease; Adrenergic beta-Agonists; Animals; Dioxoles; Disease Models, Animal; Injections, Intravenous; Isoproterenol; Male; Swine; Terbutaline; Ureter; Ureteral Obstruction

The aim of this study was to evaluate the effects of a beta3-adrenoceptor (AR) agonist (CL-316243), an alpha1-AR agonist (phenylephrine), and a loop diuretic (furosemide) on the spontaneous rhythmic contractions of the isolated canine ureter and on an acute ureteral obstruction produced by inflation of a balloon catheter in anesthetized dogs. In the isolated ureter, CL-316243 concentration dependently reduced both the amplitude and frequency of the rhythmic contractions (pD(2): 7.19 +/- 0.33), whereas phenylephrine significantly enhanced both variables (pD(2): 5.26 +/- 0.09) and furosemide reduced them only slightly. In the acute ureteral obstruction model, the intraureteral pressure (IUP) gradually rose to reach a plateau of 58.9 mm Hg after inflation of a balloon catheter within the lower ureter. Intravenous administration of CL-316243 (0.3 microg/kg) significantly reduced the elevated IUP and the resumed urine flow (UF), leading to a sustained reduction in the IUP. In contrast, the IUP continued to increase above the plateau level for 10 minutes after phenylephrine administration (10 microg/kg) and for 30 minutes after furosemide administration (1,000 microg/kg). In the phenylephrine group, the UF resumed when the IUP reached 75.8 mm Hg, and thereafter the IUP gradually decreased in parallel with the increase in the UF. From these results, we conclude that in dogs, CL-316243 reduces the IUP by allowing the UF to resume as a result of a relaxation of ureter at the obstruction site, whereas with phenylephrine, the reduction in the IUP is secondary to a resumption in the UF resulting from an induced contraction of ureter that causes an increase in hydrostatic pressure above the obstruction site.

Topics: Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Animals; Dioxoles; Diuretics; Dogs; Female; Furosemide; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Phenylephrine; Pressure; Time Factors; Ureter; Ureteral Obstruction; Urination

The objective of the present study was to evaluate the effects of a selective beta(3)-adrenoceptor agonist, (R, R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1, 3-benzodioxole-2,2-dicarboxylate (CL 316243), on the acutely obstructed ureter in anesthetized dogs. After a complete ureteral obstruction produced by the inflation of a balloon catheter placed within the left lower ureter, the intraluminal ureteral pressure gradually rose to reach a plateau of approximately 52.5 mm Hg. Intravenous administration of isoproterenol (a nonselective beta-adrenoceptor agonist; 10 microg/kg) and CL 316243 (1 microg/kg) significantly decreased this elevated ureteral pressure (by 74.1 and 77.2%, respectively), with the reduction more sustained with CL 316243 than with isoproterenol. In addition, under both isoproterenol and CL 316243, urine flow (which had been interrupted by the balloon) was resumed, resulting in further sustained decreases in ureteral pressure. The mean blood pressure decreased and heart rate increased after the administration of both drugs, but these changes were greater in the isoproterenol group than in the CL 316243 group. In contrast, i.v. administration of butylscopolamine (an anticholinergic agent; 1000 microg/kg) had no evident effects on ureteral pressure or on urine flow. The increase in left kidney weight seen after ureteral obstruction was suppressed by CL 316243. We conclude that the selective beta(3)-adrenoceptor agonist tested appears to be more useful than isoproterenol for reducing ureteral pressure above the obstructed site and for promoting ureteral relaxation and increasing urine flow around the point of obstruction in dogs.

Topics: Adrenergic beta-Agonists; Anesthesia; Animals; Blood Pressure; Butylscopolammonium Bromide; Catheterization; Dioxoles; Dogs; Female; Heart Rate; Isoproterenol; Kidney Tubules; Male; Muscarinic Antagonists; Time Factors; Ureteral Obstruction; Urodynamics