Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in salt-sensitive hypertension.
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 micromol 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 micromol; 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.
Fujita
Megumi
M
Department of Nephrology and Endocrinology, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Ando
Katsuyuki
K
Nagae
Ai
A
Fujita
Toshiro
T
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006973:Hypertension / Q000209:etiology* / Q000503:physiopathology; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D008297:Male; D009249:NADP / Q000494:pharmacology; D018384:Oxidative Stress; D011336:Probability; D011897:Random Allocation; D051381:Rats; D020303:Rats, Inbred Dahl; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000009:adverse effects*; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012965:Sodium Chloride / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology
D017382:Reactive Oxygen Species; D013481:Superoxides; D012965:Sodium Chloride; D009249:NADP