Effects of Acute l-Arginine Administration in Coronary Atherosclerosis
To the Editor:
Lerman et al1 in their interesting study reported that supplementation with l-arginine (the precursor of nitric oxide synthesis) for 6 months in patients without significant coronary artery stenosis reversed coronary small-vessel endothelial dysfunction and improved symptoms. Furthermore, it decreased plasma endothelin concentrations in patients. However, they did not examine the effects of l-arginine on epicardial coronary arteries and stenoses.
We have examined2 3 by quantitative angiography the vasomotor effects of intracoronary infusion of normal saline (2 mL/min) for 2 minutes followed by 50 and 150 μmol/min l-arginine and bolus administration of 250 μg of nitroglycerin on 38 nonstenotic epicardial coronary artery segments and 22 stenoses in patients with coronary artery disease and a positive treadmill exercise test result (≥0.1 mV ST-segment depression at between 5 and 7 metabolic equivalents [METS] using the modified Bruce protocol).
The diameter of the stenosis after saline, 50 μmol/min l-arginine, 150 μmol/min l-arginine, and nitroglycerin was 1.52±0.10, 1.60±0.1 (P<0.01 versus saline), 1.64±0.14 (P<0.01 versus saline), and 1.76±0.12 mm (P<0.01 versus saline, P<0.05 versus l-arginine), respectively. The diameter of nonstenotic segments was 2.93±0.10, 3.02±0.11 (P<0.01 versus saline), 3.14±0.12 (P<0.01 versus saline), and 3.18±0.10 mm (P<0.01 versus saline), respectively. The percentage change from baseline was 0.9±0.4%, 6.7±1.6%, 10.9±2.0%, 16.9±2.1% in stenosis diameter and 0.7±0.2%, 4.2±1.0%, 7.8±0.9%, and 9.9±1.5% in nonstenotic segment diameter for saline, 50 and 150 μmol/min l-arginine, and nitroglycerin, respectively. The diameter change after 150 μmol/min l-arginine was ≈84% of the diameter change after nitroglycerin for nonstenotic segments and 50% for stenoses.
The results of our study are consistent with stimulation of nitric oxide synthase activity by l-arginine administration. Our study provides further evidence of preserved nitric oxide synthase activity at the site of coronary stenoses. Furthermore, because this effect was also found in nonstenotic segments of diseased coronary arteries, it is either a physiological response or a pathological response requiring only minimal coronary disease. An alternative explanation for the stimulation of nitric oxide synthase would be a physiological action on vascular smooth muscle that augments its responsiveness to nitric oxide or other endogenous vasodilator mechanisms.
The substrate-deficiency hypothesis is supported by experimental evidence in hypercholesterolemic rabbits that arginine administration restores cholinergic (nitric oxide dependent) relaxation of thoracic aorta4 and also by clinical studies that show correction of endothelial dysfunction by l-arginine in the coronary microcirculation of hypercholesterolemic patients.5 Our findings further support and extend the interesting observations of Lerman et al1 and suggest that l-arginine supplementation also has a beneficial effect on diseased epicardial coronary arteries.
- Copyright © 1999 by American Heart Association
Lerman A, Burnett JC, Higano ST, Kinley LJ, Holmes DR. Long term l-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation. 1998;97:2123–2128.
Tousoulis D, Davies G, Tentolouris C, Crake T, Toutouzas P. Coronary stenosis dilatation induced by l-arginine. Lancet. 1997;349:1812–1813.
Tousoulis D, Davies GJ, Tentolouris C, Crake T, Katsimaglis G, Stefanadis C, Toutouzas P. Effects of changing the availability of the substrate for nitric oxide synthase by l-arginine administration on coronary vasomotor tone in angina patients with angiographically narrowed and in patients with normal coronary arteries. Am J Cardiol. 1998;82:1110–1113.
Cooke JP, Andon NA, Girerd XJ, Hirsch AT, Creager MA. Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation. 1991;83:1057–1062.
Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolemic patients by l-arginine. Lancet. 1991;338:1546–1550.
We read with interest the response of Tentolouris et al reporting their experience with administration of intracoronary l-arginine in humans. Their group demonstrated that intracoronary administration of l-arginine resulted in a significant increase in coronary artery diameter in stenotic as well as nonstenotic segments. Their findings are consistent with the emerging data and concept that l-arginine may serve as a therapeutic tool to improve coronary as well as peripheral vascular reactivity.
The use of l-arginine as a tool to examine the nitric oxide pathway grew into a potential role for l-arginine as a therapeutic tool in cardiovascular disease. However, the mechanism by which l-arginine improved vascular reactivity may vary between acute and chronic administration of l-arginine. The acute administration of l-arginine may exert its mechanism mainly through the nitric oxide pathway by increasing substrate bioavailability. However, there is a continuous body of evidence to suggest that additionally, chronic administration of l-arginine may improve vascular reactivity. These observations were initially termed the arginine paradox because the Km of nitric oxide synthase for l-arginine is lower than the intracellular concentration. New data are currently presented to explain this paradox. One of the main mechanisms by which l-arginine may improve endothelial function may be related to its role in antagonizing the competitive inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA). Indeed, 2 recent studies in humans demonstrated that the administration of l-arginine may exert a beneficial effect by changing the l-arginine/ADMA ratio.R1 R2
Currently, we have data that l-arginine acutely or chronically improves endothelial function in patients with hypercholesterolemia, coronary endothelial dysfunction,R3 heart failure, and intermittent claudication. Thus, new prospective studies should address the role of l-arginine therapy in the regression of atherosclerosis in humans.
Böger RH, Bode-Böger SM, Thiele W, Creutzig A, Alexander K, Frölich JC. Restoring vascular nitric oxide formation by l-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. J Am Coll Cardiol. 1998;32:1336–1344.
Böger RH, Bode-Böger SM, Szuba A, Tsao PS, Chan JR, Tangphao O, Blaschke TF, Cooke JP. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation. 1998;98:1842–1847.
Lerman A, Burnett JC Jr, Higano ST, McKinley LJ, Holmes DR Jr. Long term l-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation. 1998;97:2123–2128.