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Enhanced Vascular PI3K/Akt-NOX Signaling Underlies the Peripheral NMDAR-mediated Pressor Response in Conscious Rats

McGee, Marie A. PhD; Abdel-Rahman, Abdel A. PhD

Journal of Cardiovascular Pharmacology: May 2014 - Volume 63 - Issue 5 - p 395–405
doi: 10.1097/FJC.0000000000000059
Original Article

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.

Department of Pharmacology, Brody School of Medicine, East Carolina University, Greenville, NC.

Reprints: Abdel A. Abdel-Rahman, PhD, Department of Pharmacology, Brody School of Medicine, East Carolina University, Greenville, NC 27834 (e-mail:

Supported by National Institute of Alcohol Abuse and Alcoholism (Grants 2R01 AA07839-19 and AA07839-18S).

The authors report no conflicts of interest.

Received July 11, 2013

Accepted November 27, 2013

© 2014 by Lippincott Williams & Wilkins.