© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Elevation of an endogenous inhibitor of nitric oxide synthesis in experimental congestive heart failure
aCardiology Research Laboratory, London Health Sciences Centre, Departments of Medicine, Pharmacology and Toxicology, University of Western Ontario, Victoria Campus, 375 South Street, London, Ontario, Canada N6A 4G5
bDepartment of Clinical Pharmacology, University of Gothenburg, Gothenburg, Sweden
cCardiology Research Laboratory, Department of Physiology University of Western Ontario, London, Ontario, Canada
* Corresponding author. Tel.: (+1-519) 685 8300X5502; fax: (+1-519) 432 7367; e-mail: qfeng@julian.uwo.ca
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 µmol/l) were significantly increased compared with sham-operated controls (0.75±0.06 µmol/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 µM) (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.
KEYWORDS Asymmetric dimethylarginine (ADMA); L-Arginine; Nitric oxide synthase Inhibitor; Nitric oxide; Endothelium; Renal function; Congestive heart failure; Rat
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