Rat mesenteric arterial dilator response to 11,12-epoxyeicosatrienoic acid is mediated by activating heme oxygenase.
11,12-Epoxyeicosatrienoic acid (11,12-EET), a potent vasodilator produced by the endothelium, acts on calcium-activated potassium channels and shares biological activities with the heme oxygenase/carbon monoxide (HO/CO) system. We examined whether activation of HO mediates the dilator action of 11,12-EET, and that of the other EETs, on rat mesenteric arteries. Dose-response curves (10(-9) to 10(-6) M) to 5,6-EET, 8,9-EET, 11,12-EET, 14,15-EET, and ACh (10(-9) to 10(-4) M) were evaluated in preconstricted (10(-6) mol/l phenylephrine) mesenteric arteries (<350 microm diameter) in the presence or absence of 1) the cyclooxygenase inhibitor indomethacin (2.8 microM), 2) the HO inhibitor chromium mesoporphyrin (CrMP) (15 microM), 3) the soluble guanylyl cyclase (GC) inhibitor ODQ (10 microM), and 4) the calcium-activated potassium channel inhibitor iberiotoxin (25 nM). The vasodilator response to 11,12-EET was abolished by CrMP and iberiotoxin, whereas indomethacin and ODQ had no effect. In contrast, the effect of ACh was attenuated by ODQ but not by CrMP. The vasodilator effect of 8,9-EET, like that of 11,12-EET, was greatly attenuated by HO inhibition. In contrast, the mesenteric vasodilator response to 5,6-EET was independent of both HO and GC, whereas that to 14,15-EET demonstrated two components, an HO and a GC, of equal magnitude. Incubation of mesenteric microvessels with 11,12-EET caused a 30% increase in CO release, an effect abolished by inhibition of HO. We conclude that the rat mesenteric vasodilator action of 11,12-EET is mediated via an increase in HO activity and an activation of calcium-activated potassium channels.
Sacerdoti
David
D
Dept. of Clinical and Experimental Medicine, Univ. of Padova, Italy, Via Giustiniani 2, 35100 Padova, Italy. david.sacerdoti@unipd.it
Bolognesi
Massimo
M
Di Pascoli
Marco
M
Gatta
Angelo
A
McGiff
John C
JC
Schwartzman
Michal Laniado
ML
Abraham
Nader G
NG
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002248:Carbon Monoxide / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D008652:Mesoporphyrins / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D008652:Mesoporphyrins; D009942:Organometallic Compounds; D010069:Oxadiazoles; D010455:Peptides; D024681:Potassium Channels, Calcium-Activated; D011810:Quinoxalines; D014665:Vasodilator Agents; C427471:chromium mesoporphyrin; C476530:tricarbonylchloro(glycinato)ruthenium(II); C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C064719:iberiotoxin; D002248:Carbon Monoxide; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; C050715:8,9-epoxyeicosatrienoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D006419:Heme Oxygenase (Decyclizing); D015126:8,11,14-Eicosatrienoic Acid; D000109:Acetylcholine