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.