Journal of Applied Physiology, Vol 66, Issue 2 955-961, Copyright © 1989 by American Physiological Society
Enhanced airway responses to substance P after repeated challenge in guinea pigs
S. A. Shore and J. M. Drazen
Department of Medicine, Beth Israel Hospital, Boston, Massachusetts.
We performed three consecutive dose-response curves to rapid intravenous
infusions of substance P (SP) in anesthetized, mechanically ventilated
guinea pigs. The dose of SP required to decrease pulmonary conductance to
50% of its base-line value (ED50GL) decreased 2.8-fold (P less than 0.002)
and 3.3-fold (P less than 0.001) on the second and third dose-response
curves, respectively, compared with the first. SP did not alter airway
responses to intravenous histamine but did cause a significant (3.7-fold)
decrease in ED50GL for dose-response curves to intravenous capsaicin, an
agent that causes bronchoconstriction by release of endogenous tachykinins.
The neutral metalloendopeptidase inhibitor thiorphan (0.5 mg) and the
angiotensin-converting enzyme inhibitor captopril (1.7 mg) both caused a
marked enhancement of airway responses to SP observed on the first
dose-response curve but did not alter the enhancement of SP-induced airway
responses produced by repeated SP challenge. The anticholinergic atropine
(5 mg/kg iv), the antihistamine mepyramine (8 mg/kg iv), and the
cyclooxygenase inhibitor indomethacin (30 mg/kg ip) had no effect on the
first SP dose-response curve. Atropine and mepyramine did not prevent the
enhancement of SP responses observed with repeated challenge, but after
pretreatment with either indomethacin or acetylsalicylic acid,
dose-response curves to SP were reproducible. Our results indicate that
airway responses to intravenous SP are enhanced with repeated SP challenge
and suggest that cyclooxygenase products of arachidonic acid metabolism are
involved in the mediation of this phenomenon.
