Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone.
We tested the hypothesis that angiotensin II-induced hypertension is associated with an increase in vascular .O2- production, and characterized the oxidase involved in this process. Infusion of angiotensin II (0.7 mg/kg per d) increased systolic blood pressure and doubled vascular .O2- production (assessed by lucigenin chemiluminescence), predominantly from the vascular media. NE infusion (2.75 mg/kg per d) produced a similar degree of hypertension, but did not increase vascular .O2- production. Studies using various enzyme inhibitors and vascular homogenates suggested that the predominant source of .O2- activated by angiotensin II infusion is an NADH/NADPH-dependent, membrane-bound oxidase. Angiotensin II-, but not NE-, induced hypertension was associated with impaired relaxations to acetylcholine, the calcium ionophore A23187, and nitroglycerin. These relaxations were variably corrected by treatment of vessels with liposome-encapsulated superoxide dismutase. When Losartan was administered concomitantly with angiotensin II, vascular .O2- production and relaxations were normalized, demonstrating a role for the angiotensin type-1 receptor in these processes. We conclude that forms of hypertension associated with elevated circulating levels of angiotensin II may have unique vascular effects not shared by other forms of hypertension because they increase vascular smooth muscle .O2- production via NADH/NADPH oxidase activation.
Rajagopalan
S
S
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Kurz
S
S
Münzel
T
T
Tarpey
M
M
Freeman
B A
BA
Griendling
K K
KK
Harrison
D G
DG
D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009129:Muscle Tonus / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D005996:Nitroglycerin / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D019323:omega-N-Methylarginine
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D007093:Imidazoles; D013777:Tetrazoles; D013481:Superoxides; D000804:Angiotensin II; D019323:omega-N-Methylarginine; D000001:Calcimycin; D001120:Arginine; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D009247:NADH, NADPH Oxidoreductases; D005996:Nitroglycerin; D019808:Losartan; D000109:Acetylcholine; D009638:Norepinephrine