Leukotriene (LT) C4 or D4 may mediate pulmonary hypertension induced by hypoxia. LT have also been isolated from patients with persistent pulmonary hypertension of the newborn syndrome and the adult respiratory distress syndrome. To compare the effects of LTC4 and D4 on the pulmonary and systemic circulations, we performed dose-response studies on spontaneously breathing newborn lambs. To determine whether the hemodynamic effects of LT are mediated through alpha-adrenergic stimulation, some lambs were pretreated with the alpha-adrenergic antagonist phentolamine mesylate before LT injection. These results were compared to the effects of pretreatment with the LT receptor antagonist FPL57231. To determine whether the LT-induced decrease in cardiac output was mediated by the decrease in heart rate, other lambs had their heart rate maintained by left atrial pacing. We found that LTC4 and D4 increased systemic arterial pressure and decreased cardiac output and heart rate. However, LTD4, but not LTC4, increased pulmonary arterial pressure. The hemodynamic effects of LTC4 and LTD4 were completely blocked by FPL57231 but not by phentolamine mesylate. Maintenance of heart rate by left atrial pacing did not alter the LT-induced decrease in cardiac output. We conclude that LTC4 and D4 have similar effects on the systemic circulation. However, LTD4 produces more pulmonary vasoconstriction. Because FPL57231 did block the pulmonary vasoconstriction caused by LT, LT antagonists may be useful in treating patients with pulmonary hypertension.