Synergism between inflammatory mediators in vivo. Induction of airway hyperresponsiveness to C3a in the guinea pig.

The complement anaphylatoxin C3a causes acute bronchoconstriction after intravenous infusion in guinea pigs. At doses of 6 to 600 µg/kg, the peptide causes significant and dose-dependent increases in resistance (Rl) and decreases in dynamic compliance (Cdyn). Inhibition of serum carboxypeptidase N, the enzyme thought to be responsible for control of C3a activity in blood, by pretreating animals with dl-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MGPA), resulted in a 4-fold potentiation of the response to 200 µg/kg C3a. Responses to lower C3a doses were not significantly affected. Pretreating animals intravenously with histamine prior to administration of C3a resulted in potentiation of C3a-induced bronchoconstriction at all doses tested, decreasing the amount of C3a required to double Rl by 15-fold, from 110 to 7 µg/kg. The effect appears to be relatively specific for C3a since histamine pretreatment did not alter airway responsiveness to methacholine. Similarly, pretreatment with methacholine at...