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Characterization of the capsaicin‐sensitive component of cyclophosphamide‐induced inflammation in the rat urinary bladder
Author(s) -
Ahluwalia A.,
Maggi C.A.,
Santicioli P.,
Lecci A.,
Giuliani S.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb14845.x
Subject(s) - extravasation , chemistry , capsaicin , nk1 receptor antagonist , tachykinin receptor , methysergide , pharmacology , endocrinology , antagonist , receptor antagonist , substance p , medicine , neurogenic inflammation , receptor , neuropeptide , biochemistry , immunology
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 occuring 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 −l , 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 NK 1 receptor antagonist, RP 67,580 (0.44 mg kg −1 ) or the bradykinin B 2 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 NK 2 receptor antagonist, SR 48,968 (0.3 mg kg −1 , i.p.), the histamine H 1 receptor blocker, chlorpheniramine (10 mg kg −1 , i.p.), the 5‐HT receptor blocker, methysergide (6 mg kg −l , 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 μ m ) produced a concentration‐dependent contraction that was significantly reduced by in vitro capsaicin desensitization (10 μ m 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 NK 1 and NK 2 receptor antagonists, RP 67,580 (3 μ m ) and SR 48,968 (1 μ m ). The dose‐response curve to acrolein was also significantly inhibited by treatment with indomethacin (10 μ m ) and slightly affected by Hoe 140 (1 μ m ). 6 These findings demonstrate the contribution of CSPANs to the development of CYP‐induced cystitis. Plasma protein extravasation involves activation of tachykinin NK 1 and bradykinin B 2 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.