Recombinant human C5a (rHuC5a), produced by a synthetic gene expressed in Escherichia coli, causes a decrease in dynamic lung compliance and an increase in pulmonary resistance when injected intravenously in anesthetized mechanically ventilated guinea pigs over a dose range of 5-20 μg/kg. Intravenous injection of rHuC5a also caused an immediate decrease in mean arterial blood pressure followed by a transient increase. The purpose of this study was to determine the mediators responsible for these effects. To assess the role of histamine, plasma levels of histamine were monitored and the effects of the H1 antagonist pyrilamine were assessed. rHuC5a caused a significant increase in plasma histamine. However, the H1 antagonist did not alter the maximum or the time course of the bronchoconstrictor response indicating that histamine did not play a major role. The LTD4 antagonist L-649,923 did not inhibit the rHuC5a-induced bronchoconstriction whereas the cyclo-oxygenase inhibitor indomethacin did. Thus, to assess the role of cyclo-oxygenase products, plasma levels of thromboxane (TX) B2, prostaglandin (PG) D2 and PGF2α were monitored after injection of rHuC5a. In addition, guinea pigs were treated with either the TX synthetase inhibitor U-63557A or with the TX receptor antagonist SQ 29,548. rHuC5a challenge caused an increase in plasma concentrations of TXB2, PGD2 and PGF2α which peaked before the maximum of the bronchoconstriction. SQ 29,548 significantly inhibited the maximum of the bronchoconstrictor response, whereas U-63557A did not inhibit the maximum but did inhibit the time course of the response. The transient increase in blood pressure induced by rHuC5a involves arachidonate metabolites since it was inhibited by L-649,923, indomethacin, U-63557A and SQ 29,548. The rHuC5a-induced decrease in dynamic lung compliance and increase in pulmonary resistance in the guinea-pig is due primarily to generation of cyclo-oxygenase products, in particular thromboxane, without a contribution by histamine.