Mechanism of Central Atypical Cannabinoid Receptor GPR18‐Mediated Hypotension in Conscious Rats

Abstract

Background and objectivesVascular GPR18 activation causes vasodilation, and our preliminary findings are the first to show: (i) GPR18 expression in tyrosine hydroxylase (TH) immunoreactive neurons in the rostral ventrolateral medulla (RVLM); (ii) RVLM GPR18 activation (Abn CBD) and blockade (O‐1918) dose‐dependently reduced and increased BP, respectively, in conscious male Sprague Dawley rats. Here we tested the hypothesis that NO generation, via ERK1/2 activation, coupled with reduced reactive oxygen species (ROS) generation in RVLM underlies GPR18‐mediated hypotension. We complemented the integrative studies with signaling studies in differentiated PC12 cells (catecholamine expressing cells with neuronal phenotype) to elucidate the molecular mechanisms implicated in GPR18 signaling.Key results: Ex vivo studies, on RVLM neuronal tissues, collected during the hypotensive response elicited by intra‐RVLM GPR18 activation in conscious rats revealed increases in ERK phosphorylation and NO level and reduced ROS in RVLM while GPR18 blockade elicited opposite BP and molecular responses. In PC12 cells, GPR18 is associated with lipid rafts, and its activation replicated the molecular responses obtained in the RVLM.ConclusionGPR18 activation in the RVLM lowers BP by reducing oxidative stress and increasing NO, via ERK1/2 phosphorylation. Similar molecular findings in PC12 cells support the use of this model system in ongoing GPR18 signaling studies. Specifically, pharmacologic/genetic manipulation studies will elucidate the role of the lipid rafts and their major protein, caveolin, in GPR18 signaling.