Role of 20-hydroxyeicosatetraenoic and epoxyeicosatrienoic acids in the regulation of vascular function in a model of hypertension and endothelial dysfunction.
The objective of this study was to determine if acute inhibition of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis or reduced inactivation of epoxyeicosatrienoic acids (EETs) can correct L-N(G)-nitro-arginine-methyl-ester (L-NAME)-induced abnormal vascular reactivity in the perfused mesenteric bed and the carotid artery of spontaneously hypertensive rats (SHR). Administration of L-NAME in drinking water (80 mg/l) to SHR for 3 weeks resulted in abnormal vascular reactivity to norepinephrine and carbachol in the perfused mesenteric vascular bed and carotid artery, and significantly elevated mean arterial blood pressure (244 +/- 9 mm Hg) as compared to SHR controls drinking regular water (176 +/- 3 mm Hg). In the perfused mesenteric vascular bed, the impaired vascular responsiveness to norepinephrine was corrected by acute treatment with N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine (HET0016), an inhibitor of 20-HETE formation, but not by 1-cyclohexyl-3-dodecyl urea (CDU), an inhibitor of soluble epoxide hydrolase. Treatment with either HET0016 or CDU did not improve impaired carbachol-induced vasodilation in the perfused mesenteric vascular bed. In the isolated carotid artery, treatment with HET0016 corrected the L-NAME-induced increase in norepinephrine-induced vasoconstriction, whereas only CDU treatment could improve impaired carbachol-induced vasodilation. Results of this study indicate that vascular function in a state of compromised nitric oxide formation is differentially modulated by 20-HETE and EETs, and that treatment with HET0016 or CDU may improve vascular function in a state of high blood pressure and endothelial dysfunction.
Yousif
Mariam H M
MH
Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat, Kuwait. mariam@hsc.edu.kw
Benter
Ibrahim F
IF
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology*; D006893:Hydroxyeicosatetraenoic Acids / Q000502:physiology*; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D014652:Vascular Diseases / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
C450146:1-cyclohexyl-3-dodecylurea; D000578:Amidines; D001095:Arachidonic Acids; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; D014662:Vasoconstrictor Agents; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D014508:Urea; D002217:Carbachol; D009638:Norepinephrine