Published Online
on August 28, 2006

A more recent version of this article appeared on October 1, 2006

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Submitted on April 18, 2006
Revised on May 5, 2006

Reactive Oxygen Species Impair Sympathetic Vasoregulation in Skeletal Muscle in Angiotensin II-Dependent Hypertension

Weiying Zhao; Scott A. Swanson; Jianfeng Ye; Xilong Li; John M. Shelton; Weiguo Zhang; and Gail D. Thomas^*

From the Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.

^* To whom correspondence should be addressed. E-mail: gail.thomas{at}utsouthwestern.edu.

Abstract--Sympathetic vasoconstriction is attenuated in exercising muscle by locally generated vasodilators, including NO. Skeletal muscle also produces reactive oxygen species (ROS), such as superoxide (O₂^-), which inactivates NO. We, therefore, hypothesized that excessive ROS production would result in enhanced sympathetic vasoconstriction in exercising muscle. To increase O₂^- by activating NADPH oxidase, rats underwent chronic infusion of angiotensin II (Ang II) or unilateral renal artery stenosis (2K1C) to increase endogenous Ang II. At rest, sympathetic nerve stimulation (range: 1 to 5 Hz) evoked similar graded decreases in femoral vascular conductance (range, -34% to -66%) in rats infused with vehicle, Ang II, or norepinephrine and in 2K1C or sham-operated rats. These sympathetically mediated decreases in femoral vascular conductance were markedly attenuated during hindlimb contraction in the vehicle, norepinephrine, and sham rats (range, -3% to -26%) and to a lesser degree in the Ang II (range, -16% to -47%) and 2K1C (range, -16% to -45%) rats. In muscles from Ang II and 2K1C rats, ROS were elevated and the NADPH oxidase subunit gp91^phox was upregulated. The O₂^- scavenger tempol restored the normal attenuation of sympathetic vasoconstriction in the contracting hindlimbs of the Ang II and 2K1C rats, but this effect was prevented by pretreatment with an NO synthase inhibitor. Taken together, these data indicate that chronically elevated Ang II increases muscle ROS, which disrupts the normal NO-dependent attenuation of sympathetic vasoconstriction. These findings may have implications for muscle oxidative stress and sympathetic vasoregulation when the renin-angiotensin system is chronically activated.

Key words: angiotensin • free radicals • sympathetic nervous system • vasoconstriction • muscles

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