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 dr ug gliclazide affects diabetic endothelial dysfunction in streptozotocin-in duced diabetic rats. Gliclazide was compared with glibenclamide, ascorbic a cid, and aminoguanidine. An insulin-dependent model of diabetes was selecte d to exclude insulin-releasing effects of the drugs. Both in isolated aorti c segments and mesenteric microvessels, endothelium-dependent relaxation ev oked by acetylcholine (ACh, 1 nM to 10 mu M) was significantly reduced in v essels from diabetic animals. This impairment was reversed when the segment s were previously incubated with 100 U/ml superoxide dismutase. When strept ozotocin-induced diabetic rats were orally treated from the time of diabete s induction with gliclazide (10 mg/kg) or ascorbic acid (250 mg/kg), ACh-in duced endothelium-dependent relaxation was well preserved both in aortic se gments and mesenteric microvessels. In addition, the impaired vasodilatatio n to exogenous nitric oxide (NO) in aortic segments was also improved in gl iclazide-treated diabetic rats. On the other hand, oral treatment with glib enclamide (1 and 10 mg/kg) or aminoguanidine (250 mg/kg) did not produce si gnificant improvements in diabetic endothelial dysfunction. We conclude tha t 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 antio xidants. We propose that the mechanism involved is the inactivation of reac tive oxygen species, which are increased in diabetes probably as a result o f increased early protein glycosylation products, such as glycosylated hemo globin (HbA(1c)). These effects of gliclazide are not shared by other oral hypoglycemic agent such as glibenclamide, or by blockade of advanced glycos ylation end product (AGE) generation with aminoguanidine. (C) 2000 Elsevier Science Inc. All rights reserved.