icatibant and Cystitis

The rat urinary bladder is one of the few in vivo preparations in which kinin B1 receptor-mediated contractile responses have been described, but the nature (local or reflex) of these responses has not been characterized. We have investigated the motor effects of i.v. or topical (onto the bladder serosa) administration of the selective kinin B1 receptor agonist [des-Arg9]-bradykinin ([des-Arg9]-BK) in the normal or inflamed (cyclophosphamide-induced) urinary bladder in urethane-anaesthetized rats. In both normal and inflamed bladders [des-Arg9]-BK produced a tonic contraction of low amplitude (< 15 mmHg) with phasic contractions of high amplitude (> or = 15 mmHg) superimposed (micturition reflex contractions). In inflamed bladders, the response to [des-Arg9]-BK was more prominent than in controls. Similar observations were made after the topical administration of [des-Arg9]-BK. In order to evaluate any time-dependency in the expression of B1 receptor-mediated bladder responses, [des-Arg9]-BK was administered in separate groups of control animals at 30 and 240 min after the completion of surgical procedures required for set-up of the preparation: no bladder contraction was detected at 30 min whereas both local and reflex contractions could be elicited by [des-Arg9]-BK at 240 min after the set up. In ganglionectomized rats, the response to [des-Arg9]-BK or the selective tachykinin NK2 receptor agonist [betaAla8]NKA(4-10) was evaluated at 30 and 240 min after the set up in inflamed or in control animals. The response to [des-Arg9]-BK was greater after inflammation although a time-dependent increase was evident in both groups; in contrast, the response to [betaAla8]NKA(4-10) was similar in both groups and remained constant over the observation period. After induction of inflammation, the tonic contraction induced by [des-Arg9]-BK in ganglionectomized rats was dose-dependently reduced by the kinin B1 receptor antagonist [desArg10]Hoe 140. The contractile response (number of micturition reflex contractions) induced by [des-Arg9]-BK in normal rats with intact pelvic nerves at 240 min from the set up was not changed after the administration of the selective B2 receptor antagonist Hoe 140. These results indicate that stimulation of bladder kinin B1 receptors evokes a local, tonic-type contraction with reflex contractions superimposed in both normal and inflamed bladders, but in the latter situation the motor responses are magnified.

Topics: Administration, Topical; Anesthetics, Intravenous; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin Receptor Antagonists; Cyclophosphamide; Cystitis; Dose-Response Relationship, Drug; Ganglia, Parasympathetic; Ganglionectomy; Male; Muscle Contraction; Rats; Rats, Wistar; Receptor, Bradykinin B1; Receptors, Bradykinin; Reference Values; Tetrahydroisoquinolines; Urethane; Urinary Bladder

This study assessed the relative involvement of the two bradykinin (Bk) receptors (B1 and B2) in the viscero-visceral hyper-reflexia (VVH) and plasma extravasation observed in an animal model of cystitis. The effects of the competitive receptor antagonists des-Arg9[Leu8]-Bk (B1) and HOE 140 (B2) were tested both in prophylactic (pre-inflammation administration) and therapeutic (post-inflammation administration) scenarios. Compared with control animals, des-Arg9[Leu8]-Bk had no effect on the hyper-reflexic response of the bladder to inflammation unless it was administered 5 h after inflammation. However, HOE 140 was able to attenuate the inflammation-induced viscero-visceral hyper-reflexia (VVH) at doses of 1 mg/kg, 2 mg/kg and 7.5 mg/kg. This effect was apparent whether the drug was administered before, or after inflammation. In contrast, neither compound was effective in attenuating the intravesical plasma extravasation induced by turpentine. The data therefore suggest that the VVH and tissue inflammation responses are mediated via different mechanisms. In addition, the turpentine-induced VVH appears to be mediated, at least partially, by the B2 receptor in the early phase, with the B1 receptor only becoming important later.

Topics: Adrenergic beta-Antagonists; Animals; Bradykinin; Bradykinin Receptor Antagonists; Coloring Agents; Cystitis; Evans Blue; Female; Hyperalgesia; Rats; Rats, Wistar; Reflex, Abnormal; Urinary Bladder; Viscera

1. Cyclophosphamide (CYP) (150 mg kg-1, i.p. 0.5-48 h before) caused a time-dependent plasma protein extravasation in the rat urinary bladder with the maximal extravasation occurring at between 2 and 4 h after administration of the drug. 2. Prior capsaicin desensitization of capsaicin-sensitive primary afferent neurones (CSPANs) (50 mg kg-1, s.c., 4 days before) resulted in approximately 50% inhibition of the magnitude of the extravasation response at the 2 h time-point. 3. Intraperitoneal (i.p.) pretreatment with the tachykinin NK1 receptor antagonist, RP 67,580 (0.44 mg kg-1) or the bradykinin B2 receptor antagonist, Hoe 140 (0.13 mg kg-1) had significant inhibitory effects, giving responses of 56 +/- 6% and 39 +/- 4% of the control extravasation response to CYP treatment after 2 h. Pretreatment with the tachykinin NK2 receptor antagonist, SR 48,968 (0.3 mg kg-1, i.p.), the histamine H1 receptor blocker, chlorpheniramine (10 mg kg-1, i.p.), the 5-HT receptor blocker, methysergide (6 mg kg-1, i.p.) or the cyclo-oxygenase inhibitor indomethacin (5 mg kg-1, i.p.) had no significant effect upon the development of the extravasation response at this same time-point. 4. In rat isolated urinary bladder strips, the active metabolite of CYP, acrolein (1-300 microM) produced a concentration-dependent contraction that was significantly reduced by in vitro capsaicin desensitization (10 microM for 15 min) indicating direct stimulation of CSPANs. CYP was without appreciable effect. 5. The effect of acrolein in vitro was significantly reduced by pretreatment of the bladder with a combination of tachykinin NK1 and NK2 receptor antagonists, RP 67,580 (3 microM) and SR 48,968 (1 microM). The dose-response curve to acrolein was also significantly inhibited by treatment with indomethacin (10 microM) and slightly affected by Hoe 140 (1 microM). 6. These findings demonstrate the contribution of CSPANs to the development of CYP-induced cystitis.Plasma protein extravasation involves activation of tachykinin NKI and bradykinin B2 receptors.Activation of CSPANs in the urinary bladder is likely to be due to the conversion of CYP into its active metabolite, acrolein, and not to a direct effect of CYP upon these nerve-endings.

Topics: Acrolein; Animals; Blood Proteins; Bradykinin; Capsaicin; Cyclophosphamide; Cystitis; Dose-Response Relationship, Drug; In Vitro Techniques; Male; Neurons, Afferent; Rats; Rats, Wistar; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Urinary Bladder

The effects of the bradykinin receptor selective antagonist, Hoe 140, and of the tachykinin NK-1 receptor antagonist (+/-)CP 96,345 were investigated in a rat model of chemically-induced cystitis (intravesical instillation of xylene in female rats). Intravenous injection of bradykinin (1 mumol./kg.) or substance P (3 nmol./kg.) produced plasma protein extravasation (PPE) in the rat urinary bladder. Bradykinin response was prevented by Hoe 140 (100 nmol./kg. intravenously) and unaffected by (+/-)CP 96,345 (10 mumol./kg. intravenously). Plasma protein extravasation produced by substance P was inhibited by (+/-)CP 96,345 but unchanged by Hoe 140. Catheterization required for intravesical xylene instillation into the female rat bladder produced per se an inflammatory response which was abolished by either Hoe 140 or (+/-)CP 96,345. Intravesical instillation of xylene produced a large PPE response which was reduced by about 65% by Hoe 140 or (+/-)CP 96,345. Combined administration of the two antagonists produced an additive effect on the PPE response to xylene. We conclude that both bradykinin and tachykinins are involved in the inflammatory reaction of the rat urinary bladder to catheterization and xylene irritation.

Topics: Administration, Intravesical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Bradykinin; Cystitis; Female; Rats; Rats, Wistar; Substance P; Xylenes

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 mumol/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 mumol/l) inhibited (by about 50%) the CGRP-LI out-flow stimulated by bradykinin. These findings demonstrate the participation of bradykinin, through B2 receptors, in the genesis of detrusor hyperreflexia during cyclophosphamide-induced cystitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bradykinin; Calcitonin Gene-Related Peptide; Cystitis; Dose-Response Relationship, Drug; Female; Male; Muscle Contraction; Rats; Rats, Wistar; Receptors, Bradykinin; Receptors, Neurokinin-2; Receptors, Neurotransmitter; Urinary Bladder