Inhibition of leukotriene release in anaphylactic guinea-pig hearts by a 5-lipoxygenase inhibitor, CGS 8515.

Abstract

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.

• Authors: H B Yaacob, P J Piper
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 95 Issue 4 Pg. 1322-8 (Dec 1988) ISSN: 0007-1188 [Print] England
• PMID: 3146401 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipoxygenase Inhibitors
• Naphthoquinones
• Pyrazoles
• SRS-A
• ortho-Aminobenzoates
• methyl 2-((3,4-dihydro-3,4-dioxo-1-naphthalenyl)amino)benzoate
• 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine
• Ovalbumin
• Prostaglandin-Endoperoxide Synthases

Topics

• 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine
• Anaphylaxis (drug therapy, etiology, physiopathology)
• Animals
• Guinea Pigs
• Heart (drug effects, physiology)
• In Vitro Techniques
• Lipoxygenase Inhibitors
• Male
• Naphthoquinones (pharmacology)
• Ovalbumin (immunology)
• Perfusion
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Pyrazoles (pharmacology)
• SRS-A (metabolism)
• ortho-Aminobenzoates (pharmacology)