Dysregulation of Cerebellar Adrenomedullin Signaling During Hypertension.

Abstract

Adrenomedullin (AM) is a peptide involved in blood pressure regulation. AM activates three different 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), and extracellular signal-regulated kinases (ERK) and modulates reactive oxygen species (ROS) metabolism. Cerebellar AM, AM-binding sites, and its receptor components are altered during hypertension, although it is unknown if these alterations are associated with changes in AM signaling. Thus, we assessed AM signaling pathways in cerebellar vermis of 16-week-old Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Animals were sacrificed by decapitation, and cerebellar vermis was microdissected under stereomicroscopic control. Tissue was stimulated in vitro with AM. Then the production of cyclic guanosine monophosphate (cGMP), nitric oxide (NO) and cyclic adenosine monophosphate (cAMP) were assessed along with ERK1/2 activation and three antioxidant enzymes' activity: glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). Our findings demonstrate that in the cerebellar vermis of normotensive rats, AM increases cGMP, NO, cAMP production, and ERK1/2 phosphorylation, while decreases basal antioxidant enzyme activity. In addition, AM antagonizes angiotensin II (ANG II)-induced increment of antioxidant enzyme activity. Hypertension blunts AM-induced cGMP and NO production and AM-induced decrease of antioxidant enzyme activity. Meanwhile, AM-induced effects on cAMP production, ERK1/2 activation, and AM-ANG II antagonism were not altered in SHR rats. Our results support a dysregulation of several AM signaling pathways during hypertension in cerebellar vermis.