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

Abstract

3PN1 Ovalbumen (100 tg)-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 pM). The release was maximal at 2-3 min and detectable for as long as 10min 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 (0.03-1.0pM), an inhibitor of 5-lipoxygenase, dose-dependently inhibited ovalbumeninduced coronary vasoconstriction and leukotriene-C4 release. CGS 8515 inhibited ovalbumeninduced decreases in cardiac developed tension at 0.3 and 1.0 gm, 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 yM) 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.

Arachidonic acid metabolites alter G protein-mediated signal transduction in heart. Effects on muscarinic K+ channels.

“…For example, exogenously generated leukotrienes have been shown to alter cardiac performance. Leukotrienes (LTC 4 and LTD4) are produced in isolated heart preparations in response to antigenic stimulation (Aehringhaus et al, 1983;Levi et al, 1985;Yacoob and Piper, 1988) or during myocardial infarction (Evers et al, 1985). Although all of the leukotrienes produced during pathophysiological states may not be produced by the myocytes, leukotrienes do impinge directly on cardiac muscle, probably through specific receptors (Hogaboom et al, 1985), resulting in a negative inotropic effect (Hattori and Levi, 1984;Levi et al, 1985;Bjornsson et al, 1987).…”