Rosiglitazone, a peroxisome proliferator-activated receptor γ stimulant, abrogates diabetes-evoked hypertension by rectifying abnormalities in vascular reactivity

摘要

In addition to insulin sensitization, rosiglitazone exhibits favourable circulatory effects. In the present study, we tested the hypothesis that rosiglitazone protects against hypertension and vascular derangements caused by diabetes. Diabetes was induced by a single bolus injection of streptozotocin (50 mg/kg, i.p.). After 2 weeks, rats were started on a treatment regimen of 5 mg/kg rosiglitazone daily for a period of 6 weeks. The control group consisted of rats treated with vehicle (distilled water) for the same period of time. After 6 weeks treatment, blood pressure (BP) was recorded and serum levels of glucose, advanced glycation end-products (AGE), triglycerides, total cholesterol and low-density lipoprotein-cholesterol (LDL-C) were determined. In in vitro experiments, concentration-response curves were constructed to phenylephrine (PE), KCl and acetylcholine (ACh) in thoracic aorta rings. In addition, ACh-induced nitric oxide (NO) generation and KCl-induced intracellular Ca accumulation were determined in the aorta. Compared with values in control rats, both diastolic and systolic BP were increased in diabetic rats. Rosiglitazone treatment of diabetic rats abolished the increase in diastolic BP and significantly reduced the increased systolic BP without affecting the development of hyperglycaemia. The possibility that changes in vascular reactivity and/or lipid profile contributed to the effects of rosiglitazone on BP in diabetic rats was investigated. In aortic rings from diabetic rats, contractile responses to KCl were increased, whereas the relaxant responses to ACh were decreased. In rings from diabetic rosiglitazone-treated rats, the exaggerated response to KCl and the impaired response to ACh were abolished. Furthermore, rosiglitazone abrogated impaired ACh-stimulated NO generation in aortas isolated from diabetic rats. Diabetes in rats was accompanied by elevated levels of triglycerides, total cholesterol, LDL-C and AGE. Rosiglitazone treatment abrogated the increased levels of triglycerides, total cholesterol and LDL-C, but only partially reduced AGE levels. Collectively, these observations indicate that rosiglitazone abrogates diabetes-evoked hypertension by ameliorating detrimental changes in vascular reactivity and lipid profiles.