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Antagonism of the Cardiac Effects of Leukotriene C4 by Compound SKF 88046: Dissociation of Effects on Contractility and Coronary Flow

In the present study, we evaluated the properties of an imidodisulfamide derivative, compound SKF 88046, as an antagonist of the cardiac effects of leukotrienes (LTs). LTC4 (0.1–100 ng) caused dose-related decreases in the contractile force and coronary flow rate of the isolated guinea pig heart. SKF 88046 and the proto-typic anti-SRS (anti-slow reacting substance) compound FPL 55712 (4.8 × 10 -7 M) were equieffective in antagonizing the LTC4-induced decrease in coronary flow. On the other hand, SKF 88046 was more potent than FPL 55712 in antagonizing the negative inotropic effect of LTC4. Our findings demonstrate that SKF 88046 is an effective antagonist of the coronary constricting and myocardial depressant effects of LTC4, but that SKF 88046 preferentially antagonizes the negative inotropic effect of LTC4. This favors the hypothesis formulated by others that LT effects may be mediated by multiple receptors.