Complement 5a induces in vivo synthesis of cysteinyl leukotrienes in rats

The complement derived anaphylatoxin complement 5a (C5a) is suggested to be involved in the pathogenesis of various types of diseases including endotoxic or anaphylactic shock. Studies in our laboratory demonstrated a marked and sustained reduction in renal blood flow and glomerular filtration rate after infusion of a low dose of recombinant C5a (rC5a). Renal rC5a effects were inhibited by leukotriene (LT) and thromboxane antagonists suggesting that the effects were mediated by LT. To elucidate the mechanisms of C5a effects, we monitored the biliary excretion rate of the stable metabolite, N-acetyl-LTE4, by reversed phase high performance liquid chromatography (HPLC). Rats in the experimental group were administered rC5a intravenously at 0.5 micrograms/min for 10 min. Biliary N-acetyl-LTE4 excretion was significantly increased following rC5a infusion, 0.03 ng/microliters bile to 0.129 ng/microliters. The bile flow in the experimental group was reduced about 39% by rC5a, while bile flow of the control group increased by 20% during the observation period. Infusion of rC5a resulted in an increase of arterial hematocrit from 44.7% to 48.7%, whereas blood pressure was not significantly altered in experimental and control groups. Our results suggest the in vivo effects of C5a to be mediated by cysteinyl leukotrienes, which may be important in the pathogenesis of septic, anaphylactic or traumatic shock.