Is the balance between nitric oxide and superoxide altered in spontaneously hypertensive rats with endothelial dysfunction?
BACKGROUND
Increases in oxidant stress, i.e. excessive production of superoxide anion (O2(.-)), have been reported in different models of hypertension. This study was designed to test the hypothesis that increased O2(.-) production, more than diminished nitric oxide (NO) generation, plays a critical role in endothelial dysfunction present in spontaneously hypertensive rats (SHR).


METHODS
The study was performed in 30-week-old normotensive Wistar-Kyoto rats (WKY) and SHR. In addition, 16-week-old SHR were treated with oral irbesartan (average dose 20 mg/kg per day) for 14 weeks (SHR-I). Aortic nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) oxidase activity was determined by use of chemiluminescence with lucigenin. Aortic constitutive nitric oxide synthase (cNOS) activity was determined by measuring the conversion of L-arginine to L-citrulline. Vascular responses to acetylcholine were determined by isometric tension studies.


RESULTS
Whereas systolic blood pressure (SBP) was significantly increased in SHR compared with WKY, no differences were observed in SBP between SHR-I and WKY. In SHR compared with WKY, we found significantly greater NADH/NADPH-driven O2(.-) production, similar cNOS-mediated NO production and an impaired vasodilation in response to acetylcholine. Treated SHR had similar NADH/NADPH oxidase activity and significantly lower cNOS activity than the WKY group. Vasodilation in response to acetylcholine was improved in SHR-I.


CONCLUSIONS
These findings suggest that a diminished availability of NO secondary to an enhanced NADH/NADPH oxidase-dependent O2(.-) production may play a critical role in endothelial dysfunction of adult SHR.
Zalba
G
G
Division of Cardiovascular Pathophysiology, School of Medicine, University of Navarra, Pamplona, Spain.
Beaumont
F J
FJ
San José
G
G
Fortuño
A
A
Fortuño
M A
MA
Díez
J
J
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000201:enzymology / Q000502:physiology / Q000503:physiopathology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D000077405:Irbesartan; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology / Q000503:physiopathology*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012016:Reference Values; D013481:Superoxides / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D013777:Tetrazoles; D013481:Superoxides; D009599:Nitroprusside; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D009247:NADH, NADPH Oxidoreductases; D000077405:Irbesartan; D000109:Acetylcholine; D009638:Norepinephrine