Leukotrienes C4, D4 and E4: effects on human and guinea-pig cardiac preparations in vitro

The effects of leukotrienes C4, D4 and E4 (LT C4, D4 and E4) were studied in isolated preparations of guinea-pig and human myocardium in order to assess their contribution to cardiac dysfunction associated with systemic anaphylaxis. LT C4, D4 and E4 all caused long-lasting and dose-related decreases in the contractile force and coronary flow rate of the isolated guinea-pig heart. The rank order of potency was LT D4 greater than C4 greater than E4. The effects of LT C4 and D4 were antagonized by the anti-slow-reacting-substance compound FPL 55712. The negative inotropic effect of LT is unlikely to be secondary to the concomitant reduction in coronary flow because: 1) the same reduction in coronary flow by angiotensin II resulted in a negligible decrease in contractility and 2) the negative inotropic effect of LT also occurred in the electrically paced, noncoronary perfused left atrium and right ventricular papillary muscle of the guinea pig and in pectinate muscles obtained from surgical specimens of human right atrial appendage. LT D4 potentiated the positive chronotropic effect of histamine, supporting the concept that functional interactions occur between the various mediators of immediate hypersensitivity. The cardiac effects of pure synthetic LT are similar to those previously obtained with crude slow-reacting substance of anaphylaxis indicating that the prolonged contractile failure associated with systemic anaphylaxis largely could be due to the negative inotropic effect of LT. Because LT are released in a variety of immunological and inflammatory reactions, their potent myocardial depressant effects may play a role in cardiac dysfunction associated with these reactions.