Recombinant human C5a-induced bronchoconstriction in the guinea-pig: a histamine independent mechanism.
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 micrograms/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 PGF2 alpha 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 PGF2 alpha 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Regal
J F
JF
Department of Pharmacology, University of Minnesota, Duluth 55812.
Fraser
D G
DG
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016085:Bronchoconstrictor Agents / Q000494:pharmacology*; D043424:Carboxypeptidase B; D002268:Carboxypeptidases / Q000378:metabolism; D015936:Complement C5a / Q000494:pharmacology*; D015777:Eicosanoids / Q000097:blood; D006168:Guinea Pigs; D006632:Histamine / Q000097:blood / Q000502:physiology*; D006801:Humans; D007275:Injections, Intravenous; D015289:Leukotrienes / Q000502:physiology; D008168:Lung / Q000098:blood supply*; D008170:Lung Compliance / Q000187:drug effects*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects*
D016085:Bronchoconstrictor Agents; D015777:Eicosanoids; D015289:Leukotrienes; D011994:Recombinant Proteins; D015936:Complement C5a; D006632:Histamine; D011451:Prostaglandin-Endoperoxide Synthases; D002268:Carboxypeptidases; D043424:Carboxypeptidase B