Elevation of an endogenous inhibitor of nitric oxide synthesis in experimental congestive heart failure.
OBJECTIVE
NG,NG-dimethylarginine (asymmetric dimethylarginine, ADMA) is an important endogenous substance with potent inhibitory actions on nitric oxide (NO) synthesis. The present study was designed to determine circulating ADMA levels and endothelium-dependent, NO mediated vasodilation in a rat model of congestive heart failure (CHF).


METHODS
CHF was induced in rats by coronary artery ligation. Sham-operated rats served as normal controls. Plasma ADMA was determined by high performance liquid chromatography with fluorescence detection. Glomerular filtration rate (GFR) and renal blood flow (RBF) were measured by the clearance of inulin and p-aminohippuric acid, respectively. Endothelial function of the aorta was assessed in an organ bath.


RESULTS
Plasma levels of ADMA in rats with CHF (0.94 +/- 0.05 mumol/l) were significantly increased compared with sham-operated controls (0.75 +/- 0.06 mumol/l, p < 0.05). Plasma levels of ADMA was negatively correlated with GFR (r = -0.65, p < 0.05). Decreased endothelium-dependent relaxation to acetylcholine in the aorta of CHF was completely restored by L-arginine (300 microM) (p < 0.01) while endothelium-independent relaxation to nitroprusside was not altered. ADMA potently inhibited endothelium-dependent relaxation in thoracic aorta of normal and CHF rats. The effect of ADMA was completely antagonized by L-arginine in both groups (p < 0.01). Moreover, L-arginine improved endothelium-dependent relaxation in CHF rats in the presence of ADMA.


CONCLUSIONS
An endogenous NO synthesis inhibitor ADMA is increased in the circulation of rats with CHF. The increased plasma levels of ADMA may contribute to the decreased endothelium-dependent relaxation in CHF, which is restored by L-arginine, possibly by competitive antagonism of ADMA.
Feng
Q
Q
London Health Sciences Centre, Department of Medicine, University of Western Ontario, London, Canada. qfeng@julian.uwo.ca
Lu
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X
Fortin
A J
AJ
Pettersson
A
A
Hedner
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T
Kline
R L
RL
Arnold
J M
JM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects; D006333:Heart Failure / Q000097:blood* / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009599:Nitroprusside / Q000494:pharmacology; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D014665:Vasodilator Agents; D009599:Nitroprusside; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000109:Acetylcholine