In vitro studies have shown
LY203647 to be a selective antagonist of contractile responses to
leukotriene (LT) D4 and
LTE4 in guinea pig ileum, trachea and lung parenchyma. In pithed rat, i.v. injection of
LTD4 produced pressor responses that were selectively antagonized by
LY203647 in a dose-dependent manner [ED50 7.5 (6.0-9.5) mg/kg, i.v.]. In normal anesthetized rats and dogs,
LTD4 reduced aortic blood flow and stroke volume in association with systemic vasoconstriction, variable blood pressure responses and no change in cardiac rate.
LTD4 did not alter myocardial contractility corrected for alterations in afterload. Pretreatment of rats and dogs with
LY203647 (1-10 mg/kg, i.v.) produced dose-related inhibition of the myocardial and systemic hemodynamic effects of
LTD4, whereas coadministration of
LY203647 reversed established myocardial depression and systemic and pulmonary vasoconstriction during continuous infusion of
LTD4 in dogs.
LY203647 (10 mg/kg over 90 min, i.v.) infusion in normal dogs abolished or greatly antagonized hemodynamic responses to
LTD4 for 6 hr. In subsequent experiments,
myocardial infarct size was measured after 1 hr of occlusion of the circumflex coronary artery and 5 hr of reperfusion.
LY203647 (10 mg/kg over 90 min, i.v.) treatment did not alter cardiovascular parameters when compared to time-related alterations observed in control dogs. ST segment deviation and the intensity and duration of
cardiac arrhythmias associated with coronary artery occlusion and reperfusion also were similar between groups. Resultant
infarct sizes were 46 +/- 1 and 45 +/- 1% of the left ventricular mass placed at risk in control and LY203647-treated dogs, respectively. Present data illustrate the prominent cardiac and systemic hemodynamic effects of
LTD4 and indicate that
LY203647 produces selective and sustained antagonism of cardiovascular
LTD4 receptors. Lack of containment of
infarction by
LY203647 suggests that endogenous cysteinyl-LT do not contribute to
reperfusion injury of ischemic myocardium.