Direct and indirect effects of leukotriene D4 on the pulmonary and systemic circulations.

We investigated direct (vascular leukotriene receptor stimulation) and indirect (generation of cyclooxygenase metabolites) hemodynamic effects of leukotriene D4 (LTD4) in 6 conscious sheep. Pulmonary artery, pulmonary arterial wedge and 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 micrograms/kg of LTD4 increased mean PVR to 421% of baseline (p less than 0.001). It produced a biphasic effect on SVR that, after an initial decrease of 18% (p less than 0.05), increased to 143% of baseline (p less than 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 micrograms/kg. Dose-response curves with increasing doses of LTD4 )0.025 micrograms/kg to 0.5 micrograms/kg) revealed that the optimal dosage for maximal effect was 0.1 micrograms/kg. The effects of LTD4 (0.1 micrograms/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 less than 0.05). We conclude that 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.