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(Hypertension. 2006;48:482.)
© 2006 American Heart Association, Inc.

Original Articles

Nox2, Ca²⁺, and Protein Kinase C Play a Role in Angiotensin II-Induced Free Radical Production in Nucleus Tractus Solitarius

Gang Wang; Josef Anrather; Michael J. Glass; M. Jacqueline Tarsitano; Ping Zhou; Kelly A. Frys; Virginia M. Pickel; Costantino Iadecola

From the Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY.

Correspondence to Gang Wang, Division of Neurobiology, Weill Medical College of Cornell University, 411 East 69th St, New York, NY 10021. E-mail gaw2001{at}med.cornell.edu

The dorsomedial portion of the nucleus tractus solitarius (dmNTS) is the site of termination of baroreceptor and cardiorespiratory vagal afferents and plays a critical role in cardiovascular regulation. Angiotensin II (Ang II) is a powerful signaling molecule in dmNTS neurons and exerts some of its biological effects by modulating Ca²⁺ currents via reactive oxygen species (ROS) derived from reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase. We investigated whether a Nox2-containing NADPH oxidase is the source of the Ang II—induced ROS production and whether the signaling mechanisms of its activation require intracellular Ca²⁺ or protein kinase C (PKC). Second-order dmNTS neurons were anterogradely labeled with 4-(4-[didecylamino]styryl)-N-methylpyridinium iodide transported from the vagus and isolated from the brain stem. ROS production was assessed in 4-(4-[didecylamino]styryl)-N-methylpyridinium iodide-positive dmNTS neurons using the fluorescent dye 6-carboxy-2',7'-dichlorodihydro-fluorescein di(acetoxymethyl ester). Ang II (3 to 2000 nmol/L) increased ROS production in dmNTS neurons (EC₅₀=38.3 nmol/L). The effect was abolished by the ROS scavenger Mn (III) porphyrin 5,10,20-tetrakis (benzoic acid) porphyrin manganese (III), the Ang II type 1 receptor antagonist losartan, or the NADPH oxidase inhibitors apocynin or gp91ds-tat. Ang II failed to increase ROS production or to potentiate L-type Ca²⁺ currents in dmNTS neurons of mice lacking Nox2. The PKC inhibitor GF109203X or depletion of intracellular Ca²⁺ attenuated Ang II-elicited ROS production. We conclude that the powerful effects of Ang II on Ca²⁺ currents in dmNTS neurons are mediated by PKC activation leading to ROS production via Nox2. Thus, a Nox2-containing NADPH oxidase is the critical link between Ang II and the enhancement of Ca²⁺ currents that underlie the actions of Ang II on central autonomic regulation.

Key Words: arterial hypertension • baroreflex • calcium channels • oxidative stress • blood pressure • autonomic nervous system

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