EVIDENCE FOR THE INVOLVEMENT OF BRADYKININ IN CHEMICALLY-EVOKED CYSTITIS IN ANESTHETIZED RATS

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, (I - 10 0 nmol/kg i. v.) produced a dose-dependent blockade of the contraction of the rat urinary bladder induced by i. v. administration of bradyki nin (100 nmol/kg) without affecting the response produced by the selec tive 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 n ot modify urodynamic parameters in normal rats. Intravesical instillat ion 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 cystit is. Intraperitoneal administration of cyclophosphamide (150 mg/kg, 48 h before) decreased bladder capacity and increased micturition frequen cy. These effects of cyclophosphamide were abolished in rats pretreate d with capsaicin as adults. Hoe 140 increased bladder capacity and dec reased micturition frequency in rats pretreated with cyclophosphamide. Addition of bradykinin (10 mumol/l) to the medium in the superfused r at urinary bladder preparation evoked a prompt increase in the outflow of calcitonin gene-related peptide like immunoreactivity (CGRP-LI). H oe 140 (3 mumol/1) inhibited (by about 50%) the CGRP-LI outflow stimul ated by bradykinin. These findings demonstrate the participation of br adykinin, through B 2 receptors, in the genesis of detrusor hyperrefle xia during cyclophosphamide-induced cystitis. Capsaicin-sensitive prim ary afferent neurons are a likely target for Hoe 140 action in this mo del of experimental cystitis, as exemplified by its ability to prevent CGRP-LI outflow by bradykinin.