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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Effects of the β3-Adrenergic Receptor Agonist Disodium 5-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316243) on Bladder Micturition Reflex in Spontaneously Hypertensive Rats

Departments of Urology (L.A.L., N.J.L., E.S.R.L., X.S.), Discovery Technology Group (B.E.H., S.D.G.), and Drug Metabolism and Pharmacokinetics (C.E.), GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania

The present study investigated whether β3-adrenoceptor activation acts on the bladder afferent pathway by examination of the visceromotor reflex (VMR) and pressor responses to urinary bladder distension (UBD) and whether β3-adrenoceptor activation produces urinary bladder relaxation in hyperactive spontaneously hypertensive rats (SHRs) in comparison with their normotensive control rats [Wistar-Kyoto (WKY)]. Using the VMR responses to noxious UBD as a measure of bladder afferent signal transmission, SHRs did not present a sensitized bladder phenotype. However, reduced bladder compliance accompanied by a reduced void threshold was detected in the SHR detrusor. Furthermore, the selective β3-adrenoceptor agonist disodium 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316243) (i.v.) failed to attenuate VMR or pressor responses to UBD in either SHRs or WKY rats, but it dose-dependently inhibited rhythmic contraction (RC) in SHRs. The minimal effective dose was 0.001 mg/kg. Using the same model in WKY rats, CL-316243 did not elicit significant inhibition of contractions in the bladder RC assay. These results suggest that SHRs represent abnormal efferent/detrusor function (detrusor overactivity) without mechanosensory afferent hypersensitivity. The β3-adrenoceptor agonist CL-316243 acts on the detrusor muscle to increase urine storage in SHRs.

Address correspondence to: Dr. Xin Su, Department of Urology, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Rd., King of Prussia, PA 19406-0939. E-mail: xin.2.su{at}gsk.com

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