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An excitatory role for peripheral EP₃ receptors in bladder afferent function

Department of Urology, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania

Submitted 28 April 2008 ; accepted in final form 12 June 2008

The excitatory roles of EP₃ receptors at the peripheral afferent nerve innervating the rat urinary bladder have been evaluated by using the selective EP₃ antagonist (2E)-3-{1-[(2,4-dichlorophenyl)methyl]-5-fluoro-3-methyl-1H-indol-7-yl}-N-[(4,5-dichloro-2-thienyl)sulfonyl]-2-propenamide (DG-041). The bladder rhythmic contraction model and a bladder pain model measuring the visceromotor reflex (VMR) to urinary bladder distension (UBD) have been used to evaluate DG-041 in female rats. In addition, male rats [spontaneously hypertensive rat (SHR), Wistar-Kyoto (WKY), and Sprague-Dawley (SD)] were anesthetized with pentobarbital sodium, and primary afferent fibers in the L₆ dorsal root were isolated for recording the inhibitory response to UBD following intravenous injection of DG-041. Intravenous injection of DG-041 (10 mg/kg), a peripherally restricted EP₃ receptor antagonist, significantly reduced the frequency of bladder rhythmic contraction and inhibited the VMR response to bladder distension. The magnitude of reduction of the VMR response was not different in the different strains of rats (SD, SHR, and WKY). Furthermore, quantitative characterization of the mechanosensitive properties of bladder afferent nerves in SHR, WKY, and SD rats did not show the SHR to be supersensitive to bladder distension. DG-041 selectively attenuated responses of mechanosensitive afferent nerves to UBD, with strong suppression on the slow-conducting, high-threshold afferent fibers, with equivalent activity in the three strains. We conclude that sensitization of afferent nerve activity was not one of the mechanisms of bladder hypersensitivity in SHR. EP₃ receptors are involved in the regulation of bladder micturition and bladder nociception at the peripheral level.

EP₃; viscermotor reflex; bladder rhythmic contraction; bladder distension; afferent nerve

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