Summary
The effect of Hoe 140, a potent bradykinin B2 receptor antagonist, on the micturition reflex and detrusor hyperreflexia induced by chemical cystitis has been investigated in anaesthetized rats. Hoe 140 (1–100 nmol/kg i. v.) produced a dose-dependent blockade of the contraction of the rat urinary bladder induced by i. v. administration of bradykinin (100 nmol/kg) without affecting the response produced by the selective tachykinin NK-1 receptor agonist, [Sar9] substance P (SP) sulfone (1 nmol/kg i. v.). At doses which produce selective and long-lasting blockade of bradykinin receptors in the urinary bladder, Hoe 140 did not modify urodynamic parameters in normal rats.
Intravesical instillation of xylene in female rats decreased bladder capacity and increased micturition frequency. These effects also occurred in rats pretreated with capsaicin as adults. Hoe 140 did not modify xylene-induced cystitis. Intraperitoneal administration of cyclophosphamide (150 mg/kg, 48 h before) decreased bladder capacity and increased micturition frequency. These effects of cyclophosphamide were abolished in rats pretreated with capsaicin as adults. Hoe 140 increased bladder capacity and decreased micturition frequency in rats pretreated with cyclophosphamide.
Addition of bradykinin (10 µmol/l) to the medium in the superfused rat urinary bladder preparation evoked a prompt increase in the outflow of calcitonin gene-related peptide like immunoreactivity (CGRP-LI). Hoe 140 (3 µmol/l) inhibited (by about 50%) the CGRP-LI outflow stimulated by bradykinin.
These findings demonstrate the participation of bradykinin, through 132 receptors, in the genesis of detrusor hyperreflexia during cyclophosphamide-induced cystitis. Capsaicin-sensitive primary afferent neurons are a likely target for Hoe 140 action in this model of experimental cystitis, as exemplified by its ability to prevent CGRP-LI outflow by bradykinin.
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Maggi, C.A., Santicioli, P., Del Bianco, E. et al. Evidence for the involvement of bradykinin in chemically-evoked cystitis in anaesthetized rats. Naunyn-Schmiedeberg's Arch Pharmacol 347, 432–437 (1993). https://doi.org/10.1007/BF00165395
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DOI: https://doi.org/10.1007/BF00165395