Zusammenfassung
L-Arginin ist das Substrat für das Enzym Stickstoffmonoxidsynthase (NOS), welches für die Produktion von Stickstoffmonoxid (NO) verantwortlich ist. Stickstoffmonoxid ist ein endogenes Molekül, das eine zentrale Rolle in der Regulation von Gefäßtonus und Gefäßstruktur spielt und an vielen Prozessen beteiligt ist, die während der Entwicklung der Atherosklerose ablaufen. Es ist gezeigt worden, dass sowohl die akute als auch die chronische Gabe von L-Arginin die Endothelfunktion in Tiermodellen mit Hypercholesterinämie und Atherosklerose verbessern kann. Studien haben gezeigt, dass die diätetische Gabe von L-Arginin die NO-Bildung beim Menschen steigern kann und dadurch letztlich die Gefäßgesundheit verbessert werden kann. In dem vorliegenden Artikel wird eine Übersicht über die Studienergebnisse mit intravenöser und oraler Gabe von L-Arginin beim Menschen gegeben, die ein breites Spektrum von Dosierungen, Studiendauer und Surrogatparametern für die Endothelfunktion widerspiegeln. Die Pharmakokinetik von L-Arginin wurde untersucht, Nebenwirkungen sind selten, meistens ungefährlich und dosisabhängig. Verschiedene mögliche Wirkungsmechanismen von L-Arginin werden vorgestellt. Abschließend wird eine Bewertung von L-Arginin als Therapeutikum aus der Sicht der Klinischen Pharmakologie gegeben.
Summary
L-arginine is the substrate for the enzyme nitric oxide synthase (NOS), which is responsible for the production of nitric oxide (NO), an endogenous messenger molecule involved in many of the processes associated with the development of atherosclerosis. Acute and chronic administration of L-arginine has been shown to improve endothelial function in animal models of hypercholesterolemia and atherosclerosis. Therefore, a lot of studies were conducted to elucidate whether dietary L-arginine supplementation can augment NO production in man and thereby improve vascular health. In this review the results of studies of intravenous and oral L-arginine supplementation with a colorful spectrum of doses, study duration and surrogate parameters of endothelial function are summarized. The pharmacokinetics of L-arginine have been investigated, side effects are rare and mostly mild and dose-dependent. Several possible mechanisms of action of L-arginine are discussed. An assessment of L-arginine as a therapeutic agent from the point of view of a clinical pharmacologist is given.
Literatur
-
1
Abdelhamed A I, Reis S E, Sane D C, Brosnihan K B, Preli R B, Herrington D M.
No effect of an L-arginine-enriched medical food (HeartBars) on endothelial function and platelet aggregation in subjects with hypercholesterolemia.
Am Heart J.
2003;
145
E15
-
2
Adams M R, Forsyth C J, Jessup W, Robinson J, Celermajer D S.
Oral L-arginine inhibits platelet aggregation but does not enhance endothelium-dependent dilation in healthy young men.
J Am Coll Cardiol.
1995;
26
1054-1061
-
3
Adams M R, Jessup W, Celermajer D S.
Cigarette smoking is associated with increased human monocyte adhesion to endothelial cells: reversibility with oral L-arginine but not vitamin C.
J Am Coll Cardiol.
1997;
29
491-497
-
4
Adams M R, McCredie R, Jessup W, Robinson J, Sullivan D, Celermajer D S.
Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease.
Atherosclerosis.
1997;
129
261-269
-
5
Blum A, Hathaway L, Mincemoyer R. et al .
Oral L-arginine in patients with coronary artery disease on medical management.
Circulation.
2000;
101
2160-2164
-
6
Bode-Böger S M, Böger R H, Alfke H. et al .
L-arginine induces nitric oxide-dependent vasodilation in patients with critical limb ischemia. A randomized, controlled study.
Circulation.
1996;
93
85-90
-
7
Bode-Böger S M, Böger R H, Creutzig A. et al .
L-arginine infusion decreases peripheral arterial resistance and inhibits platelet aggregation in healthy subjects.
Clin Sci.
1994;
87
303-310
-
8
Bode-Böger S M, Böger R H, Galland A, Tsikas D, Frölich J C.
L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship.
Br J Clin Pharmacol.
1998;
46
489-497
-
9
Bode-Böger S M, Böger R H, Löffler M, Tsikas D, Brabant G, Frölich J C.
L-arginine stimulates NO-dependent vasodilation in healthy humans - effect of somatostatin pretreatment.
J Investig Med.
1999;
47
43-50
-
10
Bode-Böger S M, Muke J, Surdacki A, Brabant G, Böger R H, Frölich J C.
Oral L-arginine improves endothelial function in healthy individuals older than 70 years.
Vasc Med.
2003;
8
77-81
-
11
Böger R H.
Asymmetrisches Dimethylarginin (ADMA) als kardiovaskulärer Risikofaktor.
Dtsch Med Wochenschr.
2004;
129
820-824
-
12
Böger R H, Bode-Böger S M.
The clinical pharmacology of L-arginine.
Annu Rev Pharmacol Toxicol.
2001;
41
79-99
-
13
Böger R H, Bode-Böger S M, Brandes R P. et al .
Dietary L-arginine reduces the progression of atherosclerosis in cholesterol-fed rabbits: comparison with lovastatin.
Circulation.
1997;
96
1282-1290
-
14
Böger R H, Bode-Böger S M, Szuba A. et al .
Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia.
Circulation.
1998;
98
1842-1847
-
15
Böger R H, Bode-Böger S M, Thiele W, Creutzig A, Alexander K, Frölich J C.
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
-
16
Campisi R, Czernin J, Schoder H, Sayre J W, Schelbert H R.
L-Arginine normalizes coronary vasomotion in long-term smokers.
Circulation.
1999;
99
491-497
-
17
Ceremuzynski L, Chamiec T, Herbaczynska-Cedro K.
Effect of supplemental oral L-arginine on exercise capacity in patients with stable angina pectoris.
Am J Cardiol.
1997;
80
331-333
-
18
Chan J R, Böger R H, Bode-Böger S M. et al .
Asymmetric dimethylarginine increases mononuclear cell adhesiveness in hypercholesterolemic humans.
Arterioscler Thromb Vasc Biol.
2000;
20
1040-1046
-
19
Chin-Dusting J P, Kaye D M, Lefkovits J, Wong J, Bergin P, Jennings G L.
Dietary supplementation with L-arginine fails to restore endothelial function in forearm resistance arteries of patients with severe heart failure.
J Am Coll Cardiol.
1996;
27
1207-1213
-
20
Clarkson P, Adams M R, Powe A J. et al .
Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults.
J Clin Invest.
1996;
97
1989-1994
-
21
Creager M A, Gallagher S J, Girerd X J, Coleman S M, Dzau V J, Cooke J P.
L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans.
J Clin Invest.
1992;
90
1248-1253
-
22
Cross J M, Donald A E, Kharbanda R, Deanfield J E, Woolfson R G, MacAllister R J.
Acute administration of L-arginine does not improve arterial endothelial function in chronic renal failure.
Kidney Int.
2001;
60
2318-2323
-
23
Delles C, Schneider M P, Oehmer S, Fleischmann E H, Schmieder R E.
L-arginine-induced vasodilation of the renal vasculature is not altered in hypertensive patients with type 2 diabetes.
Diabetes Care.
2003;
26
1836-1840
-
24
Drexler H, Zeiher A M, Meinzer K, Just H.
Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine.
Lancet.
1991;
338
1546-1550
-
25
Esposito K, Nappo F, Giugliano F, Giugliano G, Marfella R, Giugliano D.
Effect of dietary antioxidants on postprandial endothelial dysfunction induced by a high-fat meal in healthy subjects.
Am J Clin Nutr.
2003;
77
139-143
-
26
Furchgott R F, Zawadzki J V.
The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.
Nature.
1980;
288
373-376
-
27
Hambrecht R, Hilbrich L, Erbs S. et al .
Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation.
J Am Coll Cardiol.
2000;
35
706-713
-
28
Hand M F, Haynes W G, Webb D J.
Hemodialysis and L-arginine, but not D-arginine, correct renal failure-associated endothelial dysfunction.
Kidney Int.
1998;
53
1068-1077
-
29
Higashi Y, Oshima T, Ozono R, Matsuura H, Kambe M, Kajiyama G.
Effect of L-arginine infusion on systemic and renal hemodynamics in hypertensive patients.
Am J Hypertens.
1999;
12
8-15
-
30
Huynh N T, Tayek J A.
Oral arginine reduces systemic blood pressure in type 2 diabetes: its potential role in nitric oxide generation.
J Am Coll Nutr.
2002;
21
422-427
-
31
Lekakis J P, Papathanassiou S, Papaioannou T G. et al .
Oral L-arginine improves endothelial dysfunction in patients with essential hypertension.
Int J Cardiol.
2002;
86
317-323
-
32
Lerman A, Burnett J C, Higano S T, McKinley L J, Holmes D R.
Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans.
Circulation.
1998;
97
2123-2128
-
33
Maxwell A J, Anderson B, Zapien M P, Cooke J P.
Endothelial dysfunction in hypercholesterolemia is reversed by a nutritional product designed to enhance nitric oxide activity.
Cardiovasc Drugs Ther.
2000;
14
309-316
-
34
Maxwell A J, Anderson B E, Cooke J P.
Nutritional therapy for peripheral arterial disease: a double-blind, placebo-controlled, randomized trial of HeartBar.
Vasc Med.
2000;
5
11-19
-
35
Otsuji S, Nakajima O, Waku S. et al .
Attenuation of acetylcholine-induced vasoconstriction by L-arginine is related to the progression of atherosclerosis.
Am Heart J.
1995;
129
1094-1100
-
36
Panza J A, Casino P R, Badar D M, Quyyumi A A.
Effect of increased availability of endothelium-derived nitric oxide precursor on endothelium-dependent vascular relaxation in normal subjects and in patients with essential hypertension.
Circulation.
1993;
87
1475-1481
-
37
Piatti P, Fragasso G, Monti L D. et al .
Acute intravenous L-arginine infusion decreases endothelin-1 levels and improves endothelial function in patients with angina pectoris and normal coronary arteriograms: correlation with asymmetric dimethylarginine levels.
Circulation.
2003;
107
429-436
-
38
Piatti P M, Monti L D, Valsecchi G. et al .
Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients.
Diabetes Care.
2001;
24
875-880
-
39
Rector T S, Bank A J, Mullen K A. et al .
Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure.
Circulation.
1996;
93
2135-2141
-
40
Sydow K, Schwedhelm E, Arakawa N. et al .
ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins.
Cardiovasc Res.
2003;
57
244-252
-
41
Theilmeier G, Chan J R, Zalpour C. et al .
Adhesiveness of mononuclear cells in hypercholesterolemic humans is normalized by dietary L-arginine.
Arterioscler Thromb Vasc Biol.
1997;
17
3557-3564
-
42
Thorne S, Mullen M J, Clarkson P, Donald A E, Deanfield J E.
Early endothelial dysfunction in adults at risk from atherosclerosis: different responses to L-arginine.
J Am Coll Cardiol.
1998;
32
110-116
-
43
Tousoulis D, Davies G, Tentolouris C, Crake T, Toutouzas P.
Coronary stenosis dilatation induced by L-arginine.
Lancet.
1997;
349
1812-1813
-
44
Wolf A, Zalpour C, Theilmeier G. et al .
Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans.
J Am Coll Cardiol.
1997;
29
479-485
-
45
Zoccali C, Bode-Böger S, Mallamaci F. et al .
Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study.
Lancet.
2001;
358
2127-2128
Professor Dr. med. Stefanie M. Bode-Böger
Direktorin des Instituts für Klinische Pharmakologie, Universitätsklinikum, Otto-von-Guericke-Universität
Leipziger Straße 44
39120 Magdeburg
Phone: 49/391/6713060
Fax: 49/391/6713062
Email: stefanie.bode-boeger@medizin.uni-magdeburg.de
