Inhibition of Ca2+/calmodulin-dependent protein kinase II, RAS-GTPase and 20-hydroxyeicosatetraenoic acid attenuates the development of diabetes-induced vascular dysfunction in the rat carotid artery.
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.
Benter
Ibrahim F
IF
Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait. ibenter@hsc.edu.kw
Yousif
Mariam H M
MH
Canatan
Halit
H
Akhtar
Saghir
S
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002339:Carotid Arteries / Q000187:drug effects* / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000517:prevention & control; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors*; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D063065:Organophosphonates / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D013449:Sulfonamides / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014652:Vascular Diseases / Q000517:prevention & control; D014661:Vasoconstriction; D014664:Vasodilation; D000096926:Benzenesulfonamides
D000578:Amidines; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D006893:Hydroxyeicosatetraenoic Acids; D020559:Monomeric GTP-Binding Proteins; D063065:Organophosphonates; D047428:Protein Kinase Inhibitors; D013311:Streptozocin; D013449:Sulfonamides; D014230:Triazoles; C436083:2-(2-oxo-2-((3,7,11-trimethyl-2,6,10-dodecatrienyl)oxy)aminoethyl)phosphonic acid, (2,2-dimethyl-1-oxopropoxy)methyl ester sodium; C000708209:HET0016; C072105:KN 93; D000096926:Benzenesulfonamides; C033020:1-aminobenzotriazole; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid