Epoxyeicosatrienoic Acid‐Induced Pulmonary Vasoconstriction is Mediated by Prostacyclin‐Induced Thromboxane‐Receptor Activation

Abstract

Epoxyeicosatrienoic acids (EETs) were reported to contribute to the increased pulmonary artery (PA) pressure of hypoxia‐induced pulmonary hypertension. EET‐induced PA contraction requires vascular endothelium, cyclooxygenase‐1 (COX‐1) activity and activation of the thromboxane receptor (TP) but not thromboxane synthesis. Here, we show that prostacyclin (PGI2) is a potential mediator of EET‐induced PA contraction. Incubation of rabbit intralobar PA rings with 5,6‐EET at its EC50 for PA contraction (0.7 μM) increased PGI2 synthesis by 2.5 ± 0.2 fold over baseline in an endothelium‐dependent manner. In isolated PA rings, incubation with SC‐560, a selective COX‐1 inhibitor, reduced 5,6‐EET‐induced PA contraction and PGI2 synthesis > 95% (P<0.01). PGI2, but not 6‐keto‐PGF1α, its breakdown product, contracted PA rings in a concentration‐dependent manner, but unlike 5,6‐EET, PGI2‐induced contraction was independent of COX‐1 and endothelium. SQ 29,548 (1 μM), a selective TP receptor antagonist, reduced PGI2‐induced PA contractions > 99% (P<0.01). PGI2‐induced PA contraction was not inhibited by CAY10441 (10 μM), a selective inhibitor of the PGI2 (IP) receptor. These results are consistent with the hypothesis that PGI2 synthesized in the vascular endothelium mediates EET‐induced contraction of intralobar PA via TP‐receptor activation. Support: NIH HL64180, HL089094.