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

Abstract

Adrenomedullin (AM) is a peptide involved in blood pressure regulation. AM exerts its effects through the activation of three receptors, the AM type 1 (AM1), type 2 (AM2) and calcitonin gene-related peptide 1 (CGRP1) receptors. AM triggers several signaling pathways such as adenylyl cyclase (AC), guanylyl cyclase (GC), extracellular signalregulated kinases (ERK) and modulates reactive oxygen species (ROS) metabolism. In brain, AM and their receptors are expressed in several localized areas, including the cerebellum. AM has been reported as an antioxidant. Recent evidence suggests the presence of an adrenomedullinergic and angiotensinergic system of physiological relevance in cerebellum vermis. To establish the role of AM in the regulation of cerebellar ROS metabolism, it was assessed the effect of AM and angiotensin II (ANG II) on three antioxidant enzymes activity: catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD), and on thiobarbituric acid reactive substances (TBARS) production in rat cerebellar vermis. The findings demonstrated that in cerebellar vermis, AM decreased and ANG II increased CAT, GPx and SOD activity and TBARS production. Likewise, AM antagonized ANG II-induced increase antioxidant enzyme activity. AM(22-50) and CGRP(8-37) blunted AM-induced decrease of antioxidant enzymes activity and TBARS production indicating that these actions are mediated through AM and CGRP1 receptors. Further, PKA inhibitor (PKAi) blunted AM action whilst apocynin and chelerythrine reverted ANG II action, suggesting that AM antioxidant action is mediated through stimulation of protein kinase A (PKA) activity, while ANG II stimulation occurs through protein kinase C/nicotinamide adenine dinucleotide phosphate oxidase (PKC/NAD(P)H oxidase) pathway. These results support the role of AM in the regulation of cerebellar antioxidant enzymes activity and suggest a physiological role for AM in cerebellum.