Characterization of substance P-induced contractions of guinea-pig trachea.
In light of current interest in substance P as a bronchoconstrictor, several pharmacologic antagonists of known mediators of anaphylaxis were tested for possible activity against this neuropeptide. Concentration-dependent contractions of the isolated guinea-pig tracheal strips to substance P (10(-8) to 10(-5) M) were elicited. These contractions were inhibited by substance P receptor antagonists, D-Arg1-D-Trp7,9-Leu11 and D-Pro2-D-Trp7,9-substance P (10(-6) to 10(-4) M). Substance P-induced contractions were not inhibited by histamine, alpha and beta adrenergic receptor antagonists or by cyclooxygenase inhibition. However, atropine enhanced contractions to substance P. Both vasoactive intestinal polypeptide (10(-7), 10(-6) and 10(-4) M) and isoproterenol (10(-7) M) were able to reverse an ongoing substance P (10(-5) M)-induced contraction. Also, at a concentration of 10(-5) M, substance P increased cyclic GMP accumulation, but had no effect on the concentration of cyclic AMP. A 15-min pretreatment with either verapamil or nifedipine (10(-8) M) had no effect on substance P-induced contractions, whereas the purported intracellular Ca++ antagonist, 8-[N,N-diethylamino]-octyl 3,4,5-trimethoxybenzoate hydrochloride (10(-4) M) produced a rightward shift of a substance P concentration-response curve. A selective calmodulin inhibitor, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (10(-4) M) failed to affect the contraction produced by 10(-5) M substance P. When guinea-pig tracheal strips were washed and allowed to re-equilibrate in 0 Ca++ buffer, the initial maximum contractions to substance P (10(-5) M) were equal for both regular (1.8 mM) Ca++ and 0 Ca++ buffer.(ABSTRACT TRUNCATED AT 250 WORDS)
Malo
P E
PE
Wasserman
M A
MA
Torphy
T J
TJ
Parris
D J
DJ
Pfeiffer
D F
DF
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D000242:Cyclic AMP / Q000032:analysis; D006152:Cyclic GMP / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D013373:Substance P / Q000494:pharmacology*; D014132:Trachea / Q000032:analysis / Q000187:drug effects* / Q000502:physiology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D013373:Substance P; D014660:Vasoactive Intestinal Peptide; D014700:Verapamil; D000242:Cyclic AMP; D006152:Cyclic GMP; D002118:Calcium