Role of AT1 receptors in permeability of the blood–brain barrier in diabetic hypertensive rats

Abstract

The precise mechanisms of vascular diseases in patients with diabetic hypertensive are not clearly understood. There are evidences of alteration in permeability of blood–brain barrier (BBB) in diabetic hypertensive rats. This study sought to examine the effect of candesartan on the systolic blood pressure and the brain endothelial barrier function and antioxidant enzymes in rat brain. Five groups of eight male Sprague–Dawley rats include: control group (gpI), diabetic hypertensive group (gpII), diabetic hypertensive group treated with candesartan (gpIII), diabetic hypertensive rats with epinephrine (gpIV) and diabetic hypertensive rats with epinephrine treated with candesartan (gpV). Diabetes was induced by single injection of 55 mg kg−1 streptozotocin (STZ) i.p. Blood glucose was measured, rats with blood glucose higher than 300 mg/dl were identified as diabetic. After induction of diabetes, rats received l-NAME (0.5 mg/ml in drinking water for 1 week) starting on the day 4 after STZ injection. Systolic blood pressure (SBP) was recorded two times, at day 0 (before starting l-NAME) and at day 7 (after l-NAME treatment). Also, body weight was measured two times, at initial time (before STZ injection) and terminal (at the last day in the experiment). On the day of acute experiment, rats were anesthetized with sodium pentobarbital (35 mg/kg, i.p.). The integrity of the BBB was investigated using Evans blue (EB) dye (4 ml/kg, 2%). Epinephrine was used (40 μg/kg) to increase the permeability of the brain. After decapitation, first the brain was removed, next homogenized and then the content of EB dye in the brain was measured. Another five groups of rats manipulated with the same manner except EB dye injection. These second group to evaluate antioxidant enzymes, reduced glutathione (GSH), lipid peroxides and superoxide dismutase (SOD) in brain homogenate. This study indicates that, in diabetic hypertensive rats, epinephrine administration leads to increase in microvascular–EB-albumin efflux to brain. However, candesartan treatment significantly attenuates this permeability to brain tissue and significantly increased GSH and SOD activity, while level of lipid peroxides was decreased significantly. The finding supports that the use of candesartan may offer a good alternative in the treatment of diabetic hypertensive subjects because it has an action that might be mediated through an antioxidant effect and beneficial effects on vascular endothelial permeability as well.