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
