Effects of the beta 3-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.
The present study investigated whether beta3-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 beta3-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 beta3-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 beta3-adrenoceptor agonist CL-316243 acts on the detrusor muscle to increase urine storage in SHRs.
Leon
Lisa A
LA
Department of Urology, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Rd., King of Prussia, PA 19406-0939, USA.
Hoffman
Bryan E
BE
Gardner
Scott D
SD
Laping
Nicholas J
NJ
Evans
Christopher
C
Lashinger
Erin S R
ES
Su
Xin
X
D058667:Adrenergic beta-3 Receptor Agonists; D000818:Animals; D004149:Dioxoles / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D022702:Receptors, Adrenergic, beta-3 / Q000502:physiology; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy / Q000503:physiopathology; D014554:Urination / Q000187:drug effects* / Q000502:physiology
D058667:Adrenergic beta-3 Receptor Agonists; D004149:Dioxoles; D022702:Receptors, Adrenergic, beta-3; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate