Effects of b-Adrenergic Stimulation on the Acutely Obstructed Ureter in Dogs

The objective of the present study was to evaluate the effects of a selective b3-adrenoceptor agonist, (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3-benzodioxole-2,2dicarboxylate (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 ;52.5 mm Hg. Intravenous administration of isoproterenol (a nonselective b-adrenoceptor agonist; 10 mg/kg) and CL 316243 (1 mg/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 mg/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 b3-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. Complete or partial ureteral obstruction can be caused by urinary calculi and can lead to edema, inflammation, and infection of the upper urinary tract, as well as to changes in ureteral functions (Biancani et al., 1976; Crowley et al., 1990). The resulting increase in intraluminal pressure in the upper urinary tract is the major cause of ureteral colic (Michaelson, 1974; Moriel et al., 1990). Previous clinical studies have shown that antispasmodics (e.g., anticholinergic agents, calcium antagonists, or papaverine) are effective for the relief of ureteral colic, and possibly for the promotion of stone passage (Ross et al., 1967; Jönsson et al., 1987; Borghi et al., 1994). However, a relaxant with more relative ureteral smooth muscle specificity compared with the cardiovascular system would result in potential clinical benefits. The autonomic nervous system is known to play an important role in modulation of ureteral motility (Schulman, 1974; Morita et al., 1987), but the functions of the parasympathetic supply to the ureter have not been well defined. Muscarinic receptors and cholinergic nerves can be demonstrated in mammalian ureters, with the innervation being rich in the intravesical ureter but scarce in the proximal ureter (del Tacca, 1978; Hernández et al., 1993), and the excitatory effects of cholinergic agonists are believed to result from both a direct muscarinic stimulation (Hernández et al., 1993) and an indirect release of catecholamines (Rose and Gillenwater, 1974). In the case of the sympathetic nervous system, adrenoceptors (ARs) and adrenergic nerves have been demonstrated in mammalian ureters (Latifpour et al., 1990; Edyvane et al., 1994), and in vitro and in vivo studies have both shown that a-AR agonists stimulate, whereas b-AR agonists inhibit, ureteral motility (Deane, 1967; Malin et al., 1970; Weiss et al., 1978; Morita et al., 1987). In the rabbit ureter, isoproterenol increases adenylate cyclase activity and the cAMP level, and these are reduced by propranolol (Weiss et