Inhibitory effects of capsazepine and SR 48968 on citric acid-induced bronchoconstriction in guinea-pigs.
We have examined the effects of capsazepine, a selective capsaicin antagonist, and SR 48968, a selective NK2 receptor antagonist, on citric acid inhalation-induced bronchoconstriction in guinea-pigs. Simultaneous inhalation of capsazepine (10 microM) significantly inhibited (by 85%) the bronchoconstriction induced by inhaled citric acid (0.4 M) but not that induced by histamine (2 mM). In capsaicin-pretreated (50 mg/kg s.c. 3 weeks earlier) guinea-pigs, citric acid failed to cause any bronchoconstriction, while the effect of histamine was uninfluenced. Furthermore, citric acid inhalation-induced bronchoconstriction was also markedly inhibited (by 65%) after pretreatment with SR 48968 (0.3 mg/kg i.v.). SR 48968 blocked the bronchoconstriction but not the hypotension evoked by neurokinin A. Therefore, these results suggest that inhalation of a low-pH solution such as citric acid can stimulate sensory neurons through a mechanism similar to that for capsaicin with regard to sensitivity to capsazepine. Tachykinins such as neurokinin A are then locally released from the terminals of sensory nerves and cause bronchoconstriction, mainly by NK2 receptor mechanisms.
Satoh
H
H
Department of Pharmacology, Karolinska Institute, Stockholm, Sweden.
Lou
Y P
YP
Lundberg
J M
JM
D000280:Administration, Inhalation; D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002951:Citrates / Q000008:administration & dosage / Q000633:toxicity*; D019343:Citric Acid; D005260:Female; D006168:Guinea Pigs; D006632:Histamine / Q000008:administration & dosage / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D008297:Male; D015288:Neurokinin A / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*
D001549:Benzamides; D002951:Citrates; D010880:Piperidines; D019343:Citric Acid; C073839:SR 48968; D006632:Histamine; D015288:Neurokinin A; C071423:capsazepine; D002211:Capsaicin