Primate myocardial and systemic hemodynamic responses to leukotriene D4: antagonism by LY171883

RA Hahn and BR MacDonald

Intravenous infusion of leukotriene D4 (LTD4; 0.1-10 micrograms/kg) produced dose-related depression of myocardial contractility, stroke volume index and mean aortic blood flow index in anesthetized monkeys. These alterations occurred in association with increments in systemic and pulmonary vascular resistances, reductions in calculated left ventricular stroke and minute work indices and relatively little or no dose-dependent change in cardiac rate, mean arterial blood pressure and mean pulmonary arterial blood pressure. Left atrial pressure did not increase in response to LTD4, although cardiac afterload was increased and myocardial contractility and stroke volume index were reduced. LTD4- induced alterations of aortic blood flow index, stroke volume index and systemic and pulmonary vascular resistances were sustained during a 60- min observation period after drug infusion. Pretreatment of monkeys with LY171883 (10 mg/kg i.v.), a selective LTD4-LTE4 receptor antagonist, inhibited the magnitude and duration of hemodynamic responses to LTD4 challenge. For example, LTD4 dose-response curves for depression of mean aortic blood flow index, stroke volume index and left ventricular stroke and minute work indices were shifted to the right approximately 10-fold by LY171883. The plasma concentration of LY171883 effective in this regard was 32 +/- 7 micrograms/ml. Attenuation of LTD4 responses by LY171883 was selective in that antagonist pretreatment did not result in concomitant reduction of vascular and cardiac responses mediated by adrenergic receptors, and LY171883 administration produced little or no change in base-line parameters. The composite data provide evidence of the presence of LT receptors in the primate cardiovascular system and suggest that LY171883 is a selective antagonist of these receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 242, Issue 1, pp. 62-69, 07/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics