n-hydroxy-n--(4-butyl-2-methylphenyl)formamidine and Vascular-Diseases

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.

Topics: Amidines; Animals; Arachidonic Acids; Blood Pressure; Carbachol; Cardiovascular Physiological Phenomena; Carotid Arteries; Endothelial Cells; Hydroxyeicosatetraenoic Acids; Hypertension; Male; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Urea; Vascular Diseases; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Diabetes causes accelerated vascular dysfunction through mechanisms that are poorly understood. This study examined the role of Ca2+/calmodulin-dependent protein kinase II (CaMKII), Ras-GTPase and 20-hydroxyeicosatetraenoic acid (20-HETE) in the development of abnormal reactivity to vasoactive agents in the carotid artery of diabetic rats. The vasoconstrictor response induced by endothelin-1 (ET-1) was significantly increased, whereas vasodilator response to carbachol was significantly reduced in the carotid artery segments of the STZ-diabetic rats. In contrast, the vasoconstrictor response to depolarization of the carotid arterial rings with 50mM KCl was similar in control and diabetic animals. Chronic intraperitoneal administration of KN-93 (5 mg/kg/alt diem), an inhibitor of CaMKII, FPTIII (1.5 mg/kg/alt diem), an inhibitor of Ras-GTPase, and inhibitors of 20-HETE formation 1-aminobenzotriazole (ABT, 50 mg/kg/alt diem) and N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine (HET0016, 2.5mg/kg/day), produced significant normalization of the altered agonist-induced vasoconstrictor and vasodilator responses without affecting blood glucose levels. All the inhibitors were administered for 4 weeks starting from the day 1 of diabetes induction. Inhibition of CaMKII, Ras-GTPase or 20-HETE formation did not affect the agonist-induced vasoconstrictor and vasodilator responses in the non-diabetic control animals. These data indicate that chronic blockade of CaMKII, Ras-GTPase or the production of 20-HETE normalizes the altered vascular reactivity to ET-1 and carbachol in the carotid artery of STZ-induced diabetic rats.

Topics: Amidines; Animals; Benzylamines; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases; Carotid Arteries; Carotid Artery Diseases; Diabetes Mellitus, Experimental; Hydroxyeicosatetraenoic Acids; Monomeric GTP-Binding Proteins; Organophosphonates; Protein Kinase Inhibitors; Rats; Rats, Wistar; Streptozocin; Sulfonamides; Triazoles; Vascular Diseases; Vasoconstriction; Vasodilation