The tachykinin NK2 receptor antagonist SR 48968 inhibits citric acid-induced airway hyperresponsiveness in guinea pigs.
Airway hyperresponsiveness is a main feature of asthma, and several lines of evidence suggest that tachykinins might be involved in the pathogenesis of airway hyperresponsiveness in rodents. We conducted a study designed to describe an original model of airway hyperresponsiveness induced by citric acid administered as aerosol to guinea pigs, and to investigate the effects of the nonpeptide neurokinin1 (NK1) and neurokinin2 (NK2)-receptor antagonists, SR 140333 and SR 48968, respectively, on the development of this airway hyperresponsiveness. Animals received thiorphan 1 mg/kg intraperitoneally and 30 min later were exposed to an aerosol of citric acid 0.4 M for 1 h. After 24 h, the animals were anesthetized and ventilated. Airway hyperresponsiveness was evidenced by significant shifts to the left of dose-response curves for intravenous acetylcholine (ACh) without a change in maximum responses to ACh. Exposure to citric acid induced an airway hyperresponsive that was abolished by chronic pretreatment with capsaicin (120 mg/kg, 5 d before citric acid exposure). SR 48968 1 mg/kg intraperitoneally, given once at 30 min before the citric acid exposure, inhibited airway hyperresponsiveness, whereas SR 140333 1 mg/kg or codeine 30 mg/kg given under similar conditions did not. The inhibition of airway hyperresponsiveness by SR 48968 did not result from functional antagonism, since SR 48968 did not affect ACh-induced bronchoconstriction, nor did it result from inhibition of tachykinin, which could have been released under the influence of ACh in hyperresponsive animals, since SR 48968 given after the exposure to aerosolized citric acid failed to inhibit airway hyperresponsiveness. In conclusion, these results show that inhaled citric acid can induce the development of an airway hyperresponsiveness in the guinea pig through a release of tachykinins, and also demonstrate that NK2-receptor stimulation plays a predominant role in the development of airway hyperresponsiveness.
Girard
V
V
Faculté de Médicine, Paris Ouest, Université Paris, France.
Yavo
J C
JC
Emonds-Alt
X
X
Advenier
C
C
D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology; D000336:Aerosols; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000503:physiopathology* / Q000517:prevention & control; D016084:Bronchoconstriction / Q000187:drug effects; D002211:Capsaicin / Q000008:administration & dosage / Q000494:pharmacology; D002951:Citrates / Q000008:administration & dosage / Q000009:adverse effects*; D019343:Citric Acid; D003061:Codeine / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011812:Quinuclidines / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000187:drug effects; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors* / Q000187:drug effects; D013237:Stereoisomerism; D015320:Tachykinins / Q000502:physiology; D015244:Thiorphan / Q000008:administration & dosage / Q000009:adverse effects
D000336:Aerosols; D001549:Benzamides; D002951:Citrates; D009294:Narcotics; D010880:Piperidines; D011480:Protease Inhibitors; D011812:Quinuclidines; D018041:Receptors, Neurokinin-2; D018039:Receptors, Tachykinin; D015320:Tachykinins; C085215:SR 140333; D019343:Citric Acid; C073839:SR 48968; D015244:Thiorphan; D000109:Acetylcholine; D002211:Capsaicin; D003061:Codeine