Role of 5,6-epoxyeicosatrienoic acid in the regulation of newborn piglet pulmonary vascular tone.
We examined the responses of newborn piglet pulmonary resistance arteries (PRAs) to 5,6-epoxyeicosatrienoic acid (5,6-EET), a cytochrome P-450 metabolite of arachidonic acid. In PRAs preconstricted with a thromboxane A(2) mimetic, 5,6-EET caused a concentration-dependent dilation. This dilation was partially inhibited by the combination of charybdotoxin (CTX) and apamin, inhibitors of large and small conductance calcium-dependent potassium (K(Ca)) channels, and was abolished by depolarization of vascular smooth muscle with KCl. Disruption of the endothelium significantly attenuated the dilation, suggesting involvement of one or more endothelium-derived vasodilator pathways in this response. The dilation was partially inhibited by nitro-L-arginine (L-NA), an inhibitor of nitric oxide synthase (NOS), but was unaffected by indomethacin, a cyclooxygenase (COX) inhibitor. The combined inhibition of NOS and K(Ca) channels with L-NA, CTX, and apamin abolished 5,6-EET-mediated dilation. Similarly, combined inhibition of NOS and COX abolished the response. We conclude that 5,6-EET is a potent vasodilator in newborn piglet PRAs. This dilation is mediated by redundant pathways that include release of nitric oxide (NO) and COX metabolites and activation of K(Ca) channels. The endothelium dependence of this response suggests that 5,6-EET is not itself an endothelium-derived hyperpolarizing factor (EDHF) but may induce the release of one or more endothelium-derived relaxing factors, such as NO and/or EDHF.
Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. mfuloria@wfubmc.edu
Mamta
M
Fuloria
Thuy K
TK
Smith
Judy L
JL
Aschner
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019335:Nitroarginine / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013552:Swine; D014655:Vascular Resistance / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014666:Vasomotor System / Q000502:physiology*
D016861:Cyclooxygenase Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D019335:Nitroarginine; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D015126:8,11,14-Eicosatrienoic Acid; D007213:Indomethacin