Coronary vasoconstriction in the rat, isolated perfused heart induced by platelet-activating factor is mediated by leukotriene C4.
Platelet-activating factor (Paf, 0.04-4.50 nmol) dose-dependently induced coronary vasoconstriction and decreased cardiac contractility in rat, isolated perfused hearts and concomitantly released leukotriene-like bioactivity into the cardiac effluent. Platelet-activating factor (0.9 nmol) induced an increase in 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), PGF2 alpha, PGE2 and thromboxane B2 (TXB2) measured by radioimmunoassay (RIA) of cardiac effluents following partial purification using C18 Sep-Paks. The leukotriene-like bioactivity released by Paf was identified as leukotriene C4 (LTC4) using a combination of isolation on reverse phase-h.p.l.c. (r.p.h.p.l.c.) and quantitation by RIA. In addition, LTB4 was also identified by r.p.h.p.l.c. and the levels, determined by RIA, were within the range having biological activity. The release of cyclo-oxygenase products by Paf was prevented by indomethacin (2.8 microM), markedly attenuated by diethylcarbamazine (7.7 mM) but unaffected by FPL 55712 (1.9 microM)-pretreatment. Furthermore, LTC4 (50 pmol) did not increase the release of the cyclo-oxygenase products measured. The release of LTB4 and LTC4 appeared to be unaffected by indomethacin pretreatment whereas diethylcarbamazine-pretreatment markedly inhibited release. The coronary vasoconstriction induced by Paf (0.9 nmol) was attenuated by pretreatment with indomethacin or diethylcarbamazine, whereas FPL 55712 caused a marked inhibition of the response. In contrast, the decrease in cardiac contractility was prevented by indomethacin or diethylcarbamazine and unaffected by FPL 55712 pretreatment. It is concluded that LTC4 may be largely responsible for the coronary vasoconstriction induced by Paf with cyclo-oxygenase products having a possible modulatory role whereas the latter appear to be involved in the Paf-induced decrease in cardiac contractility.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001127:Arginine Vasopressin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects*; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008084:Lipoxygenase / Q000378:metabolism; D008297:Male; D010972:Platelet Activating Factor / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000502:physiology*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*
D001095:Arachidonic Acids; D010972:Platelet Activating Factor; D013189:SRS-A; D001127:Arginine Vasopressin; D016718:Arachidonic Acid; D000001:Calcimycin; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases