Indomethacin and LY171883 modify porcine cardiopulmonary responses to leukotrienes

Abstract

We evaluated the effects of leukotriene (LT) C4 (0.8, 1.6, 2.4 nmol/kg), LTD4 (0.2, 1.0, 2.0 nmol/kg), and LTE4 (4.6 nmol/kg) on the cardiopulmonary system in anesthetized pigs. LTC4 and LTD4 increased mean pulmonary arterial (Ppa), mean aortic (Pma), and peak tracheal (Pt) pressures and decreased cardiac index (Cl). After indomethacin (cyclooxygenase blocker) or indomethacin + LY171883 (LTD4/LTE4 receptor antagonist), the highest doses of sulfidopeptide LTs were repeated. Indomethacin attenuated the increased Ppa and Pt, but did not affect the decreased Cl or increased Pma; LY171883 blocked or greatly attenuated the residual responses. LY171883 (without indomethacin) also blocked or greatly attenuated the LT-induced increases in Ppa and Pma and the decrease in Cl. We conclude that sulfidopeptide LTs cause potent systemic and pulmonary vasoconstriction in the anesthetized pig. Moreover, approximately two-thirds of the pulmonary arterial hypertension is indirectly mediated (i.e., cyclooxygenase products), with the residual one-third possibly due to direct LT-receptor stimulation. On the other hand, systemic vasoconstriction and decreased Cl are independent of cyclooxygenase products, and thus are likely to be directly mediated by LTs. The data support an important interaction between LT receptors and release of cyclooxygenase products.