VASCULAR ACTION OF THE HYPOGLYCEMIC AGENT GLICLAZIDE IN DIABETIC RABBITS

ATP-dependent potassium channel blockers used as hypoglycaemic agents may have effects on vascular disease in diabetes mellitus beyond their effect on blood glucose control. This study was designed to determine the effects of treatment with gliclazide on the isolated abdominal ao rta of diabetic rabbits in which endothelium-dependent relaxation is i mpaired by a mechanism involving oxygen-derived free radicals. After i nduction of diabetes with alloxan, there was no effect of gliclazide ( 10 mg.kg(-1).day(-1) orally) on blood glucose or insulin levels over a 6 week period. Hence, this permitted an examination of the vascular e ffects of gliclazide in diabetic rabbits exclusive of metabolic effect s. Acetylcholine- and nitric oxide-induced relaxation in aortae from r abbits treated with or without gliclazide were measured in the absence or presence of the nitric oxide synthase inhibitor, NG-nitro-L-argini ne (L-NAME). Diabetes was associated with significant impairment of ac etylcholine-induced endothelium-dependent relaxation of the abdominal aorta which was not significant in diabetic rabbits treated with glicl azide in vivo. Aortae from diabetic rabbits studied in the presence of L-NAME showed an exaggerated contraction to acetylcholine which was p revented in rabbits treated-with gliclazide. Gliclazide treatment did not affect the response to acetylcholine of normal rabbit aorta, and g liclazide when added in vitro had no effect on the response of diabeti c rabbit aorta, suggesting that the effect of gliclazide was specific to the abnormality arising with diabetes and was not due to an acute e ffect of the drug. These data indicate that gliclazide, aside from eit her a direct antioxidant action or an effect on insulin or glucose lev els, may ameliorate diabetic endothelial cell dysfunction.