TY - JOUR
T1 - 5,6-Epoxyeicosatrienoic acid, a novel arachidonate metabolite. Mechanism of vasoactivity in the rat
AU - Carroll, M. A.
AU - Garcia, M. P.
AU - Falck, J R
AU - McGiff, J. C.
PY - 1990
Y1 - 1990
N2 - We have reported that 5,6-epoxyeicosatrienoic acid (5,6-EET) was the only cytochrome P-450-dependent arachidonic acid (AA) epoxide to dilate the isolated, perfused caudal artery of the rat. We have investigated the mechanisms by which 5,6-EET dilates the rat-tail artery by studying the effect of deendothelialization and inhibition of AA metabolic pathways (cyclooxygenase, lipoxygenase, and cytochrome P-450 monooxygenase) on the vascular action of the epoxide. Rat isolated caudal arteries were perfused with Krebs-Henseleit solution at 37°C, pH 7.4, and gassed with 95% O2-5% CO2. Arterial tone was elevated with phenylephrine; acetylcholine (0.5 nmol) was used to detect the presence of intact, functional endothelium. Doses of 5,6-EET, from 6.25 to 25.0 nmol, were injected close-arterially. After obtaining control responses, the same doses were randomly retested after deendothelialization or in the presence of inhibitors of AA metabolism. Removal of the endothelium decreased by 70% the vasodilator responses to 5,6-EET. The endothelial dependency was a function of the epoxide interacting with cyclooxygenase of the endothelium, because indomethacin (3 μM) and aspirin (50 μM) prevented the vasodilator response to 5,6-EET while not affecting the response to acetylcholine. SKF-525A (1.1 μM) and metyrapone (150 μM) did not affect the responses to the 5,6-EET, whereas clotrimazole (0.7 μM) and nordihydroguariaretic acid (2.5 μM) had nonspecific effects, decreasing responses to 5,6-EET and acetylcholine. Because 5,6-EET failed to stimulate detectable release of prostanoids into the effluent from the caudal artery, we conclude that 5,6-EET requires conversion by cyclooxygenase for expression of its vasoactivity.
AB - We have reported that 5,6-epoxyeicosatrienoic acid (5,6-EET) was the only cytochrome P-450-dependent arachidonic acid (AA) epoxide to dilate the isolated, perfused caudal artery of the rat. We have investigated the mechanisms by which 5,6-EET dilates the rat-tail artery by studying the effect of deendothelialization and inhibition of AA metabolic pathways (cyclooxygenase, lipoxygenase, and cytochrome P-450 monooxygenase) on the vascular action of the epoxide. Rat isolated caudal arteries were perfused with Krebs-Henseleit solution at 37°C, pH 7.4, and gassed with 95% O2-5% CO2. Arterial tone was elevated with phenylephrine; acetylcholine (0.5 nmol) was used to detect the presence of intact, functional endothelium. Doses of 5,6-EET, from 6.25 to 25.0 nmol, were injected close-arterially. After obtaining control responses, the same doses were randomly retested after deendothelialization or in the presence of inhibitors of AA metabolism. Removal of the endothelium decreased by 70% the vasodilator responses to 5,6-EET. The endothelial dependency was a function of the epoxide interacting with cyclooxygenase of the endothelium, because indomethacin (3 μM) and aspirin (50 μM) prevented the vasodilator response to 5,6-EET while not affecting the response to acetylcholine. SKF-525A (1.1 μM) and metyrapone (150 μM) did not affect the responses to the 5,6-EET, whereas clotrimazole (0.7 μM) and nordihydroguariaretic acid (2.5 μM) had nonspecific effects, decreasing responses to 5,6-EET and acetylcholine. Because 5,6-EET failed to stimulate detectable release of prostanoids into the effluent from the caudal artery, we conclude that 5,6-EET requires conversion by cyclooxygenase for expression of its vasoactivity.
KW - arachidonic acid
KW - cyclooxygenase
KW - cytochrome P-450 monooxygenase
KW - epoxides
KW - vasoactivity
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U2 - 10.1161/01.RES.67.5.1082
DO - 10.1161/01.RES.67.5.1082
M3 - Article
C2 - 2121384
AN - SCOPUS:0025153829
SN - 0009-7330
VL - 67
SP - 1082
EP - 1088
JO - Circulation research
JF - Circulation research
IS - 5
ER -