Bradykinin causes inhibition of methacholine-induced bronchoconstriction in vivo in mice.
In this study the influence of bradykinin on airway responses was investigated in anaesthetised and ventilated mice. Airway resistance in mice was monitored using whole body plethysmography. Intravenous (i.v.) administration of bradykinin (4-40 microg/kg) did not cause a direct effect on airway resistance. Also pretreatment with propranolol (1 mg/kg, i.v.), atropine (1 mg/kg, i.v.) or indomethacin (5 mg/kg, i.v.) did not result in any effect of intravenous bradykinin on baseline airway resistance. However, i.v. bradykinin (4-40 microg/kg) caused a dose-dependent inhibition of the (0.5 mg/kg, i.v.) methacholine-induced bronchoconstriction, with an ED50 value of 3.4 +/- 0.4 microg/kg. The maximal inhibition of the bronchoconstrictor response to methacholine was 65.5 +/- 2.0%. The inhibition of the methacholine-induced bronchoconstriction by bradykinin could be prevented by treatment with the B2 receptor antagonist icatibant (Hoe 140, 0.13 mg/kg, i.v.). Also pretreatment with either propranolol (1 mg/kg, i.v.), L-NAME (30 mg/kg, i.v.) or indomethacin (5 mg/kg, i.v.) completely blocked the inhibition of the methacholine-induced bronchoconstriction by bradykinin. The inhibition of the methacholine-induced bronchoconstriction after bradykinin was not affected by the NK1 receptor antagonist RP 67580 (17.5 microg/kg, i.v.). In conclusion, the results of this study demonstrate that bradykinin causes a dose-dependent inhibition of the methacholine-induced bronchoconstriction in vivo in mice. This response is B2 receptor-mediated and at least involves the activation of beta-adrenoceptors and the synthesis of nitric oxide and cyclo-oxygenase products.
Folkerts
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Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, The Netherlands. G.Folkerts@PHARM.UU.NL
van Heuven-Nolsen
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Nijkamp
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D000403:Airway Resistance / Q000187:drug effects*; D000758:Anesthesia; D000818:Animals; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D016210:Methacholine Chloride / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C
D016210:Methacholine Chloride; D001920:Bradykinin