Published Online
on June 18, 2007

A more recent version of this article appeared on August 1, 2007

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Submitted on March 14, 2007
Revised on March 30, 2007

Sympathoexcitation by Oxidative Stress in the Brain Mediates Arterial Pressure Elevation in Salt-Sensitive Hypertension

Megumi Fujita; Katsuyuki Ando; Ai Nagae; and Toshiro Fujita^*

From the Department of Nephrology and Endocrinology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.

^* To whom correspondence should be addressed. E-mail: fujita-dis{at}h.u-tokyo.ac.jp.

Abstract--Central sympathoexcitation is involved in the pathogenesis of salt-sensitive hypertension. We have suggested that oxidative stress in the brain modulates the sympathetic regulation of arterial pressure. Thus, we investigated whether oxidative stress could mediate central sympathoexcitation in salt-sensitive hypertension. Five- to 6-week-old male Dahl salt-sensitive rats and salt-resistant rats were fed with a normal (0.3%) or high- (8%) salt diet for 4 weeks. In urethane-anesthetized and artificially ventilated rats, arterial pressure, renal sympathetic nerve activity, and heart rate decreased in a dose-dependent fashion, when 20 or 40 µmol of tempol, a membrane-permeable superoxide dismutase mimetic, was infused into the lateral cerebral ventricle. The same degree of reduction was noted in salt-sensitive and salt-resistant rats without salt loading. Salt loading significantly increased central tempol-induced reductions in arterial pressure (-29.1±4.8% versus -10.6±3.3% at 40 µmol; P<0.01), sympathetic nerve activity (-18.7±2.0% versus -7.1±1.8%; P<0.01), and heart rate (-10.7±2.8% versus -2.0±0.7%; P<0.05) in salt-sensitive rats but not in salt-resistant rats. Intracerebroventricular diphenyleneiodonium, a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, also elicited significantly greater reduction in each parameter in salt-loaded salt-sensitive rats. Moreover, salt loading increased reduced nicotinamide-adenine dinucleotide phosphate-dependent superoxide production in the hypothalamus in salt-sensitive rats but not in salt-resistant rats. In addition, reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits p22^phox, p47^phox, and gp91^phox mRNA expression significantly increased in the hypothalamus of salt-loaded salt-sensitive rats. In conclusion, in salt-sensitive hypertension, increased oxidative stress in the brain, possibly via activation of reduced nicotinamide-adenine dinucleotide phosphate oxidase, may elevate arterial pressure through central sympathoexcitation.

Key words: salt-sensitive hypertension • oxidative stress • brain • hypertension • salt • sympathetic nervous system • Dahl rat

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