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20-Hydroxyeicosatetraenoic acid is a vasoconstrictor in the newborn piglet pulmonary microcirculation

Departments of ¹Pediatrics, ²Physiology and Pharmacology, and ³Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Submitted 14 October 2003 ; accepted in final form 6 April 2004

20-Hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P-450 metabolite of arachidonic acid, is a vasoconstrictor in the systemic circulation and a vasodilator in the adult pulmonary circulation. Little is known about the vasoactive properties of 20-HETE in the newborn pulmonary circulation. The objectives of this study were to determine the vascular effects of 20-HETE and to explore the signaling mechanism(s) that mediate these effects in newborn pulmonary resistance-level arteries (PRA). Our findings demonstrate that, in contrast to the adult pulmonary circulation where 20-HETE mediates vasodilation, it causes constriction in newborn PRA at resting tone. Furthermore, inhibition of cyclooxygenase (COX) with indomethacin augments 20-HETE-induced constriction. The enhanced constrictor response to 20-HETE under conditions of COX inhibition is abolished in endothelium-disrupted PRA, suggesting that 20-HETE either stimulates endothelium-derived COX to release a counteracting vasodilator or is rapidly metabolized by COX to a less potent vasoconstrictor. 20-HETE-induced constriction is significantly inhibited by blocking calcium-dependent K⁺ (K_Ca) channels and the thromboxane-PGH₂ receptor. Altogether, our data indicate that the vascular actions of 20-HETE are partially mediated via the activation of K_Ca channels and are significantly modulated by interactions with the COX-prostaglandin pathway.

cytochrome P-450; cyclooxygenase; calcium-dependent channels; thromboxane-PGH₂ receptor; pulmonary resistance arteries

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