Effect of Valsartan on Cerebellar Adrenomedullin System Dysregulation During Hypertension

Abstract

Adrenomedullin (AM) and its receptors components, calcitonin-receptor-like receptor (CRLR), and receptor activity-modifying protein (RAMP1, RAMP2, and RAMP3) are expressed in cerebellum. Cerebellar AM, AM binding sites and receptor components are altered during hypertension, suggesting a role for cerebellar AM in blood pressure regulation. Thus, we assessed the effect of valsartan, on AM and its receptor components expression in the cerebellar vermis of Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Additionally, we evaluated AM action on superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activity, and thiobarbituric acid reactive substances (TBARS) production in cerebellar vermis. Animals were treated with valsartan or vehicle for 11 days. Rats were sacrificed by decapitation; cerebellar vermis was dissected; and AM, CRLR, RAMP1, RAMP2, and RAMP3 expression was quantified by Western blot analysis. CAT, SOD, and GPx activity was determined spectrophotometrically and blood pressure by non-invasive plethysmography. We demonstrate that AM and RAMP2 expression was lower in cerebellum of SHR rats, while CRLR, RAMP1, and RAMP3 expression was higher than those of WKY rats. AM reduced cerebellar CAT, SOD, GPx activities, and TBARS production in WKY rats, but not in SHR rats. Valsartan reduced blood pressure and reversed the altered expression of AM and its receptors components, as well the loss of AM capacity to reduce antioxidant enzyme activity and TBARS production in SHR rats. These findings demonstrate that valsartan is able to reverse the dysregulation of cerebellar adrenomedullinergic system; and they suggest that altered AM system in the cerebellum could represent the primary abnormality leading to hypertension.

The FAAH Inhibitor URB597 Modulates Lipid Mediators in the Brain of Rats with Spontaneous Hypertension

“…These antioxidants are involved in the elimination of ROS. Glutathione peroxidase and lipophilic vitamins have been shown to be [ 4 , 5 ] effective for actively protecting membrane phospholipids against peroxidation. Reduction in the level of non-enzymatic antioxidants is thought to arise from the oxidation of these compounds by ROS, given that ROS production is typically elevated in hypertension [ 4 ].…”

“…NADPH oxidase activity has been shown to be enhanced by activation of AT1 receptors in animals with hypertension [ 4 ]. Hypertension also promotes a reduction in activity of antioxidant enzymes such as Cu-Zn-SOD, CAT, GSH-Px, and GSH level [ 4 , 5 ]. The transcription factor Nrf2 plays an important role in maintaining the proper level of antioxidant proteins.…”

“…The brain tissue is also characterized by a high content of polyunsaturated fatty acids (PUFAs), which increases susceptibility to oxidative modifications [ 8 ]. Consequently, an increased production of lipid peroxidation products has been observed in the paraventricular nucleus of the hypothalamus and in the cerebellar vermis of hypertensive rats [ 4 , 5 ]. Subsequent research has demonstrated that antioxidant therapy promotes the reduction of blood pressure in the hypothalamus of spontaneously hypertensive rats (SHRs), and that these effects are mediated by reduced oxidative stress and inflammation [ 5 ].…”

Adrenomedullin and Angiotensin II in Rat Cerebellar Vermis: Reactive Oxygen Species Production

“…Therefore, hypertension tiggers a dysregulation in the AM antioxidant capacity. The absence of AM response on the basal activity of antioxidant enzymes in the cerebellar vermis of SHR rats could be due to a pattern change in AM receptors components expression previously reported in the cerebellar vermis during hypertension [31]. Furthermore, oral administration of the antihypertensive compound, valsartan, was able to reduce peripheral blood pressure and reversed changes in cerebellar expression of AM, its receptors components, antioxidant enzyme activity and TBARS production of hypertensive rats [14,15,31]; indicating that these alterations represent the primary abnormality leading to hypertension; therefore reversion with peripheral administration of an antihypertensive, may represents a strategy to compensate the primary abnormality in blood pressure control and opens the possibility of a novel mechanism in antihypertensive therapy.…”

“…Indeed, AM decreased basal antioxidant enzymes activity: catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD), suggesting that AM can reduce ROS production in the cerebellar vermis, and thereby decreasing the activation of signaling cascades activated by these molecules. This decrease in antioxidant enzyme activity in cerebellar vermis indicates that AM is capable of reducing ROS production, because antioxidant enzymes activity reduction was accompanied by a decrease in lipid peroxidation measured as thiobarbituric acid reactive substances (TBARS) production [14,15,31]. This action was mediated via stimulation of both AM and CGRP1, receptors.…”