Differential effects of leukotrienes C₄, D₄, and E₄ in the pulmonary and systemic vasculature of sheep

We investigated the comparative direct and cyclooxygenase-mediated effects of the constituents of slow-reacting substance of anaphylaxis (SRS-A), i.e., leukotriene C₄ (LTC₄), leukotriene D₄ (LTD₄) and leukotriene E₄ (LTE₄) on pulmonary and systemic haemodynamics of sheep. In 20 conscious sheep, measurements of pulmonary vascular resistance (Rpv) and systemic vascular resistance (Rsv) were obtained before and after a rapid intravenous injection of LTC₄ (0.1 μg.kg^-1), LTD₄ (0.1 μg.kg^-1) and LTE₄ (1 μg.kg^-1). The same protocol was carried out after pretreatment with the leukotriene antagonist FPL-57231 or the cyclooxygenase inhibitor indomethacin. LTD₄ increased mean Rpv to 421% of baseline (p<0.001) and had a biphasic effect on mean Rsv, which, following an initial decrease of 18% (p<0.05), increased to 143% of baseline (p<0.05). LTC₄ and LTE₄ had no significant efffects on Rpv, while they increased mean Rsv to 144% and 143% of baseline, respectively (p<0.05). This effect was not prreceded by a decrease in Rsv. FPL-57231 completely blocked the effects of LTC₄, LTD₄ and LTE₄ on Rsv, and of LTD₄ on Rpv. Indomethacin had no effect on LTC₄, LTD₄ and LTE₄-induced initial increases in mean Rsv, while it prevented the LTD₄-induced initial decrease in mean Rsv. Indomethacin also prevented the LTD₄-induced increase in Rpv. A dose-response curve (0.05, 0.1, 0.5 and 1 μg.kg^-1) demonstrated that in raising Rsv, LTE₄ was approximately 10 times less potent than LTC₄ and LTD₄. We conclude that: a) LTC₄, LTD₄ and LTE₄ have differential effects on pulmonary and systemic circulations of sheep, b) the effects of LTC₄ and LTE₄ are mediated directly by vascular leukotriene receptor stimulation, and c) LTD₄ has both direct and indirect (cyclooxygenase mediated) vascular effects.