Abstract

Cleavage of the complement protein C5 by activation of the complement system yields a low molecular weight fragment, C5a, historically referred to as anaphylatoxin. Among the biological activities of C5a is the ability to contrast isolated smooth muscle. This report is concerned with initial studies identifying mediators responsible for C5a-induced contraction of isolated guinea-pig aortic rings. C5a, purified from yeast-activated guinea-pig serum, caused a concentration-related contraction of the isolated guinea-pig aorta. The H1 antagonist diphenhydramine partially inhibited the response of the aorta to C5a, indicating that released histamine was, at least in part, responsible for the contraction. 5,8,11,14-Eicosatetraynoate, an inhibitor of both the lipoxygenase and cyclooxygenase pathway of arachidonate metabolism, inhibited the C5a-induced aortic contraction to an even greater extent than diphenhydramine, suggesting that products of arachidonate metabolism also play a role in the contraction. The cyclooxygenase inhibitors aspirin and indomethacin did not inhibit the C5a-induced aortic contraction, yet a combination of aspirin and diphenhydramine or indomethacin and diphenhydramine completely inhibited the aortic response to C5a. The presence of aspirin did not affect the ability of diphenhydramine to inhibit the response of the aorta to exogenous histamine, thus suggesting that cyclooxygenase products were not affecting the reactivity of histamine at the target smooth muscle. These studies indicate that both histamine and cyclooxygenase products are mediators responsible for C5a-induced aortic contraction.