Protection against bradykinin-induced bronchoconstriction in asthmatic patients by neurokinin receptor antagonist.
Axon reflex mechanisms may be involved in the pathogenesis of asthma, but there has been no direct evidence that endogenous tachykinins cause bronchoconstriction in asthmatic subjects. We have studied the effect of a tachykinin receptor antagonist (FK-224) on bronchoconstriction induced by inhalation of bradykinin in asthmatic patients. In a double-blind, placebo-controlled, crossover trial, ten subjects with stable asthma were given FK-224 (4 mg) or placebo by inhalation 20 min before challenge with bradykinin (0-1250 micrograms/ml, five breaths of each concentration) given with 5 min intervals. Bradykinin caused dose-dependent bronchoconstriction in all subjects. FK-224 significantly opposed the bronchoconstrictor effect; the geometric mean of the cumulative concentration required to elicit a 35% fall in specific airway conductance was 5.3 micrograms/ml after placebo and 40 micrograms/ml after FK-224 (p < 0.001). Inhalation of bradykinin caused coughing in three subjects, which was inhibited by FK-224 in all three. Antagonism of the tachykinin receptor by FK-224 greatly inhibited both bronchoconstriction and coughing induced by bradykinin in asthmatic patients, suggesting that tachykinin release from the airway sensory nerves is involved in responses to bradykinin. Tachykinin receptor antagonists may be useful in the treatment of asthma.
Ichinose
M
M
First Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
Nakajima
N
N
Takahashi
T
T
Yamauchi
H
H
Inoue
H
H
Takishima
T
T
D000280:Administration, Inhalation; D000328:Adult; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology*; D001920:Bradykinin; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D010919:Placebos; D015320:Tachykinins / Q000037:antagonists & inhibitors*
D010456:Peptides, Cyclic; D010919:Placebos; D015320:Tachykinins; C075570:FK 224; D001920:Bradykinin