Epoxyeicosatrienoic acids and dihydroxyeicosatrienoic acids are potent vasodilators in the canine coronary microcirculation

Christine L. Oltman, Neal L. Weintraub, Mike VanRollins, Kevin C. Dellsperger

Research output: Contribution to journalArticle

189 Citations (Scopus)

Abstract

Cytochrome P450 epoxygenases convert arachidonic acid into 4 epoxyeicosatrienoic acid (EET) regioisomers, which were recently identified as endothelium-derived hyperpolarizing factors in coronary blood vessels. Both EETs and their dihydroxyeicosatrienoic acid (DHET) metabolites have been shown to relax conduit coronary arteries at micromolar concentrations, whereas the plasma concentrations of EETs are in the nanomolar range. However, the effects of EETs and DHETs on coronary resistance arterioles have not been examined. We administered EETs and DHETS to isolated canine coronary arterioles (diameter, 90.0±3.4 μm; distending pressure, 20 mm Hg) preconstricted by 30% to 60% of the resting diameter with endothelin. All 4 EET regioisomers produced potent, concentration-dependent vasodilation (EC50 values ranging from -12.7 to -10.1 log [M]) and were approximately 1000 times more potent than reported in conduit coronary arteries. The vasodilation produced by 14,15-EET was not attenuated by removal of the endothelium and indicated a direct action of 14,15-EET on microvascular smooth muscle. Likewise, 14,15-DHET, 11,12-DHET, 8,9-DHET, and the δ- lactone of 5,6-EET produced extremely potent vasodilation (EC50 values ranging from -15.8 to -13.1 log [M]). The vasodilation produced by these eicosanoids was highly potent in comparison to that produced by other vasodilators, including arachidonic acid (EC50 = -7.5 log [M]). The epoxide hydrolase inhibitor, 4-phenylchalone oxide, which blocked the conversion of [3H]14,15-EET to [3H]14,15-DHET by canine coronary arteries, did not alter arteriolar dilation to 11,12-EET; thus, the potent vasodilation induced by EETs does not require formation of DHETs. In contrast, charybdotoxin (a K(Ca) channel inhibitor) and KCl (a depolarizing agent) blocked vasodilation by 11,12-EET and 11,12-DHET. We conclude that EETs and DHETs potently dilate canine coronary arterioles via activation of K(Ca) channels. The preferential ability of these compounds to dilate resistance blood vessels suggests that they may be important regulators of coronary circulation.

Original languageEnglish (US)
Pages (from-to)932-939
Number of pages8
JournalCirculation research
Volume83
Issue number9
DOIs
StatePublished - Nov 2 1998

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Microcirculation
Vasodilator Agents
Vasodilation
Canidae
Acids
Coronary Vessels
Arterioles
Charybdotoxin
Arachidonic Acid
Endothelium
Blood Vessels
Epoxide Hydrolases
Coronary Circulation
Eicosanoids
Endothelins
Lactones
Cytochrome P-450 Enzyme System
Oxides
Smooth Muscle
Dilatation

Keywords

  • Arachidonic acid
  • Coronary microcirculation
  • Dihydroxyeicosatrienoic acids
  • Endothelium-derived hyperpolarizing factor
  • Epoxyeicosatrienoic acids

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Epoxyeicosatrienoic acids and dihydroxyeicosatrienoic acids are potent vasodilators in the canine coronary microcirculation. / Oltman, Christine L.; Weintraub, Neal L.; VanRollins, Mike; Dellsperger, Kevin C.

In: Circulation research, Vol. 83, No. 9, 02.11.1998, p. 932-939.

Research output: Contribution to journalArticle

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abstract = "Cytochrome P450 epoxygenases convert arachidonic acid into 4 epoxyeicosatrienoic acid (EET) regioisomers, which were recently identified as endothelium-derived hyperpolarizing factors in coronary blood vessels. Both EETs and their dihydroxyeicosatrienoic acid (DHET) metabolites have been shown to relax conduit coronary arteries at micromolar concentrations, whereas the plasma concentrations of EETs are in the nanomolar range. However, the effects of EETs and DHETs on coronary resistance arterioles have not been examined. We administered EETs and DHETS to isolated canine coronary arterioles (diameter, 90.0±3.4 μm; distending pressure, 20 mm Hg) preconstricted by 30{\%} to 60{\%} of the resting diameter with endothelin. All 4 EET regioisomers produced potent, concentration-dependent vasodilation (EC50 values ranging from -12.7 to -10.1 log [M]) and were approximately 1000 times more potent than reported in conduit coronary arteries. The vasodilation produced by 14,15-EET was not attenuated by removal of the endothelium and indicated a direct action of 14,15-EET on microvascular smooth muscle. Likewise, 14,15-DHET, 11,12-DHET, 8,9-DHET, and the δ- lactone of 5,6-EET produced extremely potent vasodilation (EC50 values ranging from -15.8 to -13.1 log [M]). The vasodilation produced by these eicosanoids was highly potent in comparison to that produced by other vasodilators, including arachidonic acid (EC50 = -7.5 log [M]). The epoxide hydrolase inhibitor, 4-phenylchalone oxide, which blocked the conversion of [3H]14,15-EET to [3H]14,15-DHET by canine coronary arteries, did not alter arteriolar dilation to 11,12-EET; thus, the potent vasodilation induced by EETs does not require formation of DHETs. In contrast, charybdotoxin (a K(Ca) channel inhibitor) and KCl (a depolarizing agent) blocked vasodilation by 11,12-EET and 11,12-DHET. We conclude that EETs and DHETs potently dilate canine coronary arterioles via activation of K(Ca) channels. The preferential ability of these compounds to dilate resistance blood vessels suggests that they may be important regulators of coronary circulation.",
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