title: Enhanced vascular PI3K/Akt-NOX signaling underlies the peripheral NMDAR-mediated pressor response in conscious rats.
abstract: The molecular mechanisms for peripheral N-methyl-D-aspartate receptor (NMDAR)-mediated vascular oxidative stress and pressor response are not known. We conducted integrative (in vivo) and ex vivo biochemical studies to test the hypothesis that reactive oxygen species (ROS)-dependent calcium influx, triggered by the activation of vascular kinases, underlies the NMDAR-mediated pressor response. Pharmacological inhibition of phosphoinositide 3-kinase (PI3K)/Akt (wortmannin, 15 μg/kg), protein kinase C (chelerythrine: 5 mg/kg, intravenous), Ca²⁺ influx (nifedipine, 0.35 or 0.75 mg/kg), or NADPH oxidase (NOX: apocynin, 5 mg/kg) attenuated the peripheral NMDAR-mediated pressor response in conscious male Sprague-Dawley rats. NMDAR activation enhanced the phosphorylation of Akt, ERK1, JNK and p38 (Western blot), and NOX activity in vascular tissues collected during the pressor response caused by NMDA infusion (180 μg·kg⁻¹·min⁻¹, 30 minutes). Furthermore, ex vivo studies showed that wortmannin, chelerythrine, or apocynin abrogated the NMDAR-mediated vascular nitric oxide (NO) and ROS generation and NOX activation in the vasculature. These findings implicate vascular PI3K/Akt-protein kinase C signaling in the peripheral NMDAR-mediated increases in vascular NO and NOX activation (ROS), which ultimately lead to calcium influx and pressor response in conscious rats.
authors: Department of Pharmacology, Brody School of Medicine, East Carolina University, Greenville, NC.
authors: Marie A
authors: MA
authors: McGee
authors: Abdel A
authors: AA
authors: Abdel-Rahman
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D010525:Peripheral Nerves / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C