Prevention of endothelial dysfunction in streptozotocin-induced diabetic rats by gliclazide treatment.
The aim of the present work was to analyze whether the oral hypoglycemic drug gliclazide affects diabetic endothelial dysfunction in streptozotocin-induced diabetic rats. Gliclazide was compared with glibenclamide, ascorbic acid, and aminoguanidine. An insulin-dependent model of diabetes was selected to exclude insulin-releasing effects of the drugs. Both in isolated aortic segments and mesenteric microvessels, endothelium-dependent relaxation evoked by acetylcholine (ACh, 1 nM to 10 microM) was significantly reduced in vessels from diabetic animals. This impairment was reversed when the segments were previously incubated with 100 U/ml superoxide dismutase. When streptozotocin-induced diabetic rats were orally treated from the time of diabetes induction with gliclazide (10 mg/kg) or ascorbic acid (250 mg/kg), ACh-induced endothelium-dependent relaxation was well preserved both in aortic segments and mesenteric microvessels. In addition, the impaired vasodilatation to exogenous nitric oxide (NO) in aortic segments was also improved in gliclazide-treated diabetic rats. On the other hand, oral treatment with glibenclamide (1 and 10 mg/kg) or aminoguanidine (250 mg/kg) did not produce significant improvements in diabetic endothelial dysfunction. We conclude that gliclazide reverses the endothelial dysfunction associated with diabetes. This effect appears to be due not to the metabolic actions of the drug but rather to its antioxidant properties, as it can be mimicked by other antioxidants. We propose that the mechanism involved is the inactivation of reactive oxygen species, which are increased in diabetes probably as a result of increased early protein glycosylation products, such as glycosylated hemoglobin (HbA(1c)). These effects of gliclazide are not shared by other oral hypoglycemic agent such as glibenclamide, or by blockade of advanced glycosylation end product (AGE) generation with aminoguanidine.
Vallejo
S
S
Unidad de Investigación y Servicio de Geriatría, Hospital Universitario de Getafe, Spain.
Angulo
J
J
Peiró
C
C
Sánchez-Ferrer
A
A
Cercas
E
E
Llergo
J L
JL
Nevado
J
J
Sánchez-Ferrer
C F
CF
Rodríguez-Mañas
L
L
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005907:Gliclazide / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008638:Mesenteric Arteries; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D009569:Nitric Oxide / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D007004:Hypoglycemic Agents; D009569:Nitric Oxide; D005907:Gliclazide; D000109:Acetylcholine