Direct and Indirect Effects of Leukotriene D4 on the Pulmonary and Systemic Circulations

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Abstract
Direct (vascular leukotriene receptor stimulation) and indirect (generation of cyclooxygenase metabolites) hemodynamic effects of leukotriene D4 (LTD4) were investigated in 6 conscious sheep. Pulmonary artery, pulmonary arterial wedge, systemic arterial pressures and cardiac output were measured. From these parameters, pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) were calculated before and immediately after a rapid injection of LTD4 into the pulmonary artery. Injection of 0.1 .mu.g/kg of LTD4 increased mean PVR to 421% of baseline (P < 0.001). It produced a biphasic effect on SVR that, after an initial decrease of 18% (P < 0.05), increased to 143% of baseline (P < 0.05). Both PVR and SVR returned to baseline within 10 min. The same results were obtained when the dose of LTD4 was increased to 0.5 .mu.g/kg. Dose-response curves with increasing doses of LTD4 (0.025 .mu.g/kg-0.5 .mu.g/kg) revealed that the optimal dosage for maximal effect was 0.1 .mu.g/kg. The effects of LTD4 (0.1 .mu.g/kg) on the pulmonary circulation were completely blocked by the SRS-A antagonist, FPL-57231, as well as by indomethacin. In the systemic circulation, FPL-57231 blocked the biphasic effects of LTD4, on SVR, whereas indomethacin prevented the initial decrease without attenuating the subsequent increase in mean SVR (135% of baseline, P < 0.05). There are direct and indirect hemodynamic effects of LTD4: the systemic vasoconstrictor response is directly related to vascular leukotriene receptor stimulation, whereas activation of cyclooxygenase pathway products is responsible for the pulmonary vasoconstrictor and systemic depressor responses.