Contribution of histamine and prostanoids to bronchoconstriction provoked by inhaled bradykinin in atopic asthma.
Bradykinin, a nonapeptide cleavage product of high molecular weight kininogen, is a potent bronchoconstrictor agonist in asthma; however, its mechanism of action is not known. Since bradykinin has been shown to stimulate mediator release from mast cells and augment the release of prostanoids, we have examined the effect of a selective histamine H1 receptor antagonist, terfenadine and a potent cyclooxygenase inhibitor, flurbiprofen on bronchoconstriction provoked by inhaled bradykinin in asthma. As a bronchial provocation procedure bradykinin challenge was repeatable to within 1 doubling dilution. In nine atopic asthmatic subjects, terfenadine 180 mg, when compared to placebo, increased the geometric mean provocation concentration of inhaled agonist required to reduce FEV1 by 20% of baseline (PC20) from 0.7 to greater than 22.9 mg/ml for histamine (P less than 0.01) and 0.3 to 0.5 mg/ml for bradykinin (P less than 0.01). In a further nine atopic asthmatics, flurbiprofen 150 mg when compared to placebo produced a small but significant protection of the airways against bradykinin, geometric mean PC20 increasing from 0.40 to 0.79 mg/ml (P less than 0.05). We conclude that bradykinin is a potent bronchoconstrictor agonist in asthma, being approximately 9.5 times more potent than histamine in molar terms. Pharmacological intervention with terfenadine and flurbiprofen led to a significant protection of the airways against the constrictor effect of bradykinin but the effect in each case was small. Thus, while histamine and prostanoids may contribute as mediators of bradykinin-induced bronchoconstriction, they are unlikely to account for the majority of the response.
Polosa
R
R
Immunopharmacology Group, Medicine 1 Level D, Southampton General Hospital, England.
Phillips
G D
GD
Lai
C K
CK
Holgate
S T
ST
D000328:Adult; D001249:Asthma / Q000503:physiopathology* / Q000517:prevention & control; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001920:Bradykinin / Q000276:immunology*; D001985:Bronchial Provocation Tests; D005260:Female; D005480:Flurbiprofen / Q000494:pharmacology*; D006632:Histamine / Q000276:immunology*; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010919:Placebos; D016593:Terfenadine
D001559:Benzhydryl Compounds; D006634:Histamine H1 Antagonists; D010919:Placebos; D005480:Flurbiprofen; D016593:Terfenadine; D006632:Histamine; D001920:Bradykinin