Mechanism of action of cerebral epoxyeicosatrienoic acids on cerebral arterial smooth muscle.
Microsomal preparations of cat brain incubated with [14C]arachidonic acid produced epoxyeicosatrienoic acids (EETs) that eluted with the same retention times as synthetically prepared 5,6-, 8,9-, and 11,12-EETs. These compounds dilated serotonin-preconstricted, pressurized cat cerebral arteries in a dose-dependent fashion. Epoxide formation was not found in mitochondrial fractions and was dependent on the presence of NADPH. The maximum effects of 8,9-EET and 11,12-EET were greater than those of 5,6-EET. The cellular basis of this vasodilation was further investigated by examining the effects of 8,9-EET and 11,12-EET on K+ channel activity in vascular muscle cells freshly isolated from cat cerebral arteries. Both 8,9-EET and 11,12-EET increased the frequency of opening, mean open time, and open-state probability of a 98-pS K+ channel recorded in the cell-attached mode with 145 mM KCl in the pipette and 4.7 mM KCl in the bath. Blockade of K+ channel activity with tetraethylammonium attenuated the vasodilatory effects of 11,12-EET on serotonin-preconstricted cat cerebral arteries. These results suggest that endogenously formed EETs may participate in local regulation of cerebral blood flow by dilating cerebral arteries through a mechanism that involves activation of K+ channels.
Gebremedhin
D
D
Department of Physiology, Medical College of Wisconsin, Milwaukee 53266.
Ma
Y H
YH
Falck
J R
JR
Roman
R J
RJ
VanRollins
M
M
Harder
D R
DR
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002415:Cats; D002536:Cerebral Arteries / Q000187:drug effects*; D004594:Electrophysiology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008861:Microsomes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011188:Potassium / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology
D015221:Potassium Channels; D014665:Vasodilator Agents; D016718:Arachidonic Acid; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; C050715:8,9-epoxyeicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid; D011188:Potassium