Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in obesity-induced hypertension.
BACKGROUND
Obesity is one of the major risk factors for cardiovascular disease and is often associated with increased oxidative stress and sympathoexcitation. We have already suggested that increased oxidative stress in the brain modulates the sympathetic regulation of arterial pressure in salt-sensitive hypertension, which is often associated with obesity. The present study was performed to determine whether oxidative stress could mediate central sympathoexcitation in the initial stage of obesity-induced hypertension.


RESULTS
Four-week-old male Sprague-Dawley rats were fed a high-fat (45% kcal as fat) or low-fat (10% kcal as fat) diet for 6 weeks. Fat loading elicited hypertension and sympathoexcitation, along with visceral obesity. In urethane-anesthetized and artificially ventilated rats, arterial pressure and renal sympathetic nerve activity decreased in a dose-dependent fashion when 53 or 105 mumol/kg tempol, a membrane-permeable superoxide dismutase mimetic, was infused into the lateral cerebral ventricle. Central tempol reduced arterial pressure and renal sympathetic nerve activity to a significantly greater extent in high-fat diet-fed hypertensive rats than in low-fat diet-fed normotensive rats. Intracerebroventricular apocynin or diphenyleneiodonium, a reduced NADPH oxidase inhibitor, also elicited markedly greater reductions in arterial pressure and renal sympathetic nerve activity in the high-fat diet-fed rats. In addition, fat loading increased NADPH oxidase activity and NADPH oxidase subunit p22(phox), p47(phox), and gp91(phox) mRNA expression in the hypothalamus.


CONCLUSIONS
In obesity-induced hypertension, increased oxidative stress in the brain, possibly via activation of NADPH oxidase, may contribute to the progression of hypertension through central sympathoexcitation.
Nagae
Ai
A
Department of Nephrology and Endocrinology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Fujita
Megumi
M
Kawarazaki
Hiroo
H
Matsui
Hiromitsu
H
Ando
Katsuyuki
K
Fujita
Toshiro
T
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D018738:Hexamethonium / Q000494:pharmacology; D006973:Hypertension / Q000209:etiology*; D007031:Hypothalamus / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000378:metabolism; D007668:Kidney / Q000294:innervation; D008297:Male; D019255:NADPH Oxidases; D009638:Norepinephrine / Q000652:urine; D009765:Obesity / Q000150:complications*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000502:physiology*
D000098:Acetophenones; D003497:Cyclic N-Oxides; D013113:Spin Labels; D013481:Superoxides; D018738:Hexamethonium; C056165:acetovanillone; D019255:NADPH Oxidases; C001803:tempol; D009638:Norepinephrine