Role of arachidonate metabolites in C5a-induced bronchoconstriction.
The complement cleavage product, C5a, causes a bronchoconstriction in the guinea pig as evidenced by a decrease in dynamic lung compliance and an increase in pulmonary resistance. Previous studies had demonstrated that the antihistamine pyrilamine and the cyclooxygenase inhibitor indomethacin inhibited the C5a-induced bronchoconstriction but the leukotriene (LT)D4 antagonist L-649,923 did not. As an extension of those studies, the purpose of the present study was to determine the contribution of specific cyclooxygenase products and/or LTB4 in mediating C5a-induced bronchoconstriction. To assess the role of the various potential mediators, plasma levels of thromboxane (TX)B2, prostaglandin (PG)D2 and PGF2 alpha were monitored. In addition, guinea pigs were treated either with the TX synthetase inhibitor U-63557A, treated with the TX receptor antagonist SQ 29,548 or made tachyphylactic to the bronchoconstrictor actions of LTB4. C5a challenge caused an increase in plasma concentrations of TXB2, which peaked before the maximum of the bronchoconstriction. However, no significant increase in plasma concentrations of PGD2 or PGF2 alpha was seen. Both U-63557A at 80 mg/kg and SQ 29,548 significantly inhibited the C5a-induced bronchoconstriction, whereas 10 mg/kg of U-63557A did not. The inability of 10 mg/kg of U-63557A to inhibit the response could be explained by both incomplete inhibition of TX synthesis as well as possibly by the increased plasma concentrations of the potent bronchoconstrictor PGD2, which occurred with C5a challenge in the presence of U-63557A. In animals tachyphylactic to LTB4, the maximum of the C5a-induced bronchoconstriction was no different from control.(ABSTRACT TRUNCATED AT 250 WORDS)
Regal
J F
JF
Department of Pharmacology, University of Minnesota-Duluth.
D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001572:Benzofurans / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001980:Bronchi / Q000187:drug effects; D003182:Complement C5 / Q000037:antagonists & inhibitors / Q000502:physiology*; D015936:Complement C5a; D015237:Dinoprost; D005231:Fatty Acids, Unsaturated; D006168:Guinea Pigs; D006834:Hydrazines / Q000494:pharmacology; D007275:Injections, Intravenous; D007975:Leukotriene B4 / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D015230:Prostaglandin D2; D011457:Prostaglandins D / Q000097:blood; D011460:Prostaglandins F / Q000097:blood; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D001095:Arachidonic Acids; D001572:Benzofurans; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003182:Complement C5; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011457:Prostaglandins D; D011460:Prostaglandins F; D007975:Leukotriene B4; D016718:Arachidonic Acid; D013929:Thromboxane B2; D015936:Complement C5a; C045749:SQ 29548; D015237:Dinoprost; D013930:Thromboxane-A Synthase; C039936:furegrelate; D015230:Prostaglandin D2