EPOXYEICOSATRIENOIC ACIDS AND DIHYDROXYEICOSATRIENOIC ACIDS ARE POTENT VASODILATORS IN THE CANINE CORONARY MICROCIRCULATION

Cytochrome P-450 epoxygenases convert arachidonic acid into 4 epoxyeic osatrienoic 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 conce ntrations, whereas the plasma concentrations of EETs are in the nanomo lar range. However, the effects of EETs and DHETs on coronary resistan ce arterioles have not been examined. We administered EETs and DHETs t o isolated canine coronary arterioles (diameter, 90.0+/-3.4 mu m; dist ending pressure, 20 mm Hg) preconstricted by 30% to 60% of the resting diameter with endothelin. All 4 EET regioisomers produced potent, con centration-dependent vasodilation (EC50 values ranging from -12.7 to - 10.1 log [M]) and were approximately 1000 times more potent than repor ted in conduit coronary arteries. The vasodilation produced by 14,15-E ET was not attenuated by removal of the endothelium and indicated a di rect action of 14,15-EET on microvascular smooth muscle. Likewise, 14, 15-DHET, 11,12-DHET, 8,9-DHET, and the delta-lactone of 5,6-EET produc ed extremely potent vasodilation (EC50 values ranging from -15.8 to -1 3.1 log [M]). The vasodilation produced by these eicosanoids was highl y potent in comparison to that produced by other vasodilators, includi ng arachidonic acid (EC50=-7.5 log [M]). The epoxide hydrolase inhibit or, 4-phenylchalone oxide, which blocked the conversion of [H-3]14,15- EET to [H-3]14,15-DHET by canine coronary arteries, did not alter arte riolar 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 vaso dilation by 11,12-EET and 11,12-DHET. We conclude that EETs and DHETs potently dilate canine coronary arterioles via activation of K-Ca chan nels. The preferential ability of these compounds to dilate resistance blood vessels suggests that they may be important regulators of coron ary circulation.