Aldose reductase inhibitors zopolrestat and ferulic acid alleviate hypertension associated with diabetes: effect on vascular reactivity

Abstract

This study investigated the effect of aldose reductase (AR) inhibitors on hypertension in diabetes. Diabetes was induced with streptozotocin, while AR inhibitors zopolrestat and ferulic acid were administered at 2 weeks after streptozotocin treatment and for 6 weeks afterwards. Then, blood pressure (BP) and serum level of glucose were determined. Concentration–response curves for phenylephrine (PE), KCl, and acetylcholine (ACh) were obtained in isolated aorta. In addition, ACh-induced NO and reactive oxygen species (ROS) generation in aorta and histopathology were examined. Compared with the control animals, diabetes increased diastolic and systolic BP. AR inhibitors reduced diastolic BP elevation without affecting the developed hyperglycaemia. Diabetes increased the contractile response of aorta to KCl, and decreased the relaxation response to Ach, while administering AR inhibitors prevented an impaired response to ACh. Incubation of aorta isolated from diabetic animals with AR inhibitors did not affect the impaired relaxation response to ACh. In addition, AR inhibitors negated the impaired Ach-stimulated NO generation seen in aorta isolated from diabetic animals. Furthermore, diabetes was accompanied with marked infiltration of leukocytes in aortic adventitia, endothelial cell pyknosis, and increased ROS formation. AR inhibitors reduced leukocyte infiltration and inhibited endothelial pyknosis and ROS formation. In conclusion, AR inhibitors negate diabetes-evoked hypertension via ameliorating impaired endothelial relaxation and NO production.