Inhibition of leukotriene release in anaphylactic guinea-pig hearts by a 5-lipoxygenase inhibitor, CGS 8515.
1. Ovalbumen (100 micrograms)-induced coronary vasoconstriction and decrease in cardiac developed tension were studied in isolated perfused hearts from sensitized guinea-pigs. Leukotriene-like material released in the cardiac effluent was assayed against synthetic leukotriene C4 (LTC4). 2. LTC4 was released in a time-dependent fashion, and release was enhanced when hearts were challenged in the presence of indomethacin (2.8 microM). The release was maximal at 2-3 min and detectable for as long as 10 min following ovalbumen challenge. Immunoreactive (ir) thromboxane-B2 (TxB2) was also detected in cardiac effluent which had been partially purified using C18 Sep-Paks. 3. CGS 8515 (0.03-1.0 microM), an inhibitor of 5-lipoxygenase, dose-dependently inhibited ovalbumen-induced coronary vasoconstriction and leukotriene-C4 release. CGS 8515 inhibited ovalbumen-induced decreases in cardiac developed tension at 0.3 and 1.0 microM, but did not antagonize coronary vasoconstriction induced by synthetic LTC4. 4. The release of cyclo-oxygenase products following ovalbumen challenge was not inhibited by CGS 8515, but was markedly inhibited by indomethacin (2.8 microM) pretreatment. 5. We conclude that leukotrienes have a major role in guinea-pig cardiac anaphylaxis, and that CGS 8515 has a cardio-protective action. The results obtained in these experiments in vitro show that CGS 8515 is a potent and selective 5-lipoxygenase inhibitor.
Yaacob
H B
HB
Department of Pharmacology, Royal College of Surgeons of England, London.
Piper
P J
PJ
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000707:Anaphylaxis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D000818:Animals; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors; D008297:Male; D009285:Naphthoquinones / Q000494:pharmacology*; D010047:Ovalbumin / Q000276:immunology; D010477:Perfusion; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D013189:SRS-A / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D016859:Lipoxygenase Inhibitors; D009285:Naphthoquinones; D011720:Pyrazoles; D013189:SRS-A; D062367:ortho-Aminobenzoates; C055523:methyl 2-((3,4-dihydro-3,4-dioxo-1-naphthalenyl)amino)benzoate; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D010047:Ovalbumin; D011451:Prostaglandin-Endoperoxide Synthases