Effects of L-Arginine Metabolism and Supplementation on Nitric Oxide, Slides of Public Health

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Content:

•L-Arginine metabolism•Nitric oxide

•Synthases•Dimethylarginines•Effects

•Arginine Supplementation

•Infusion/ Oral•Endothelial Function

•Epidemiology

Source of Arginine

L-Arginine is considered a semi-essential amino acid: it becomesessential in growing children, duringpregnancy or after injury. A Western diet provides about 4-6g/day of which 40-50% is absorbed.

•The liver produces considerable

amounts of arginine during the ureacycle, but little is available forsynthesis.

• The intestines produce citrulline

which is converted by other tissues(kidney, 80%) into L-arginine whichis then made available to othertissues.

Nitric Oxide Synthase

Three Isoforms

Neuronal (constitutive, calcium dependent)

Endothelial (constitutive, calcium dependent)

Macrophages (inducible, calcium independent). Can lead to highlevels of NO being formed.

Nitric Oxide Effects

(via formation of cGMP)

Relaxes smooth muscle Inhibits platelet aggregation andactivation Neurotransmitter Tumoricidal and bactericidal agentfrom macrophages (excess candamage healthy tissue)

• The explanation may involve the

presence of naturally occurringinhibitors of NOS (ADMA and NMA).These two analogues of L-arginineplus SDMA are also competitors forthe y

transport system that delivers

L-arginine to NOS.

Structure of L-arginine and Circulatory Analogues

NH

NH

2

C NH CH

2

CH

2

CH

2

CH

NH

2

COOH

L-ARGININE

L-NMA

ADMA

SDMA

NH

CHNH

3

C NH CH

2

CH

2

CH

2

CH

NH

2

COOH

NH

N

CH

3

CH

3

C NH

CH

2

CH

2

CH

2

CH

NH

2

COOH

C

N

NH

CH

3

CH

3

NH

CH

2

CH

2

CH

2

CH

NH

2

COOH

• The methylated analogues are removed

by renal excretion or catabolism•DDAH type I associated with neuralNOS•DDAH type II associated withendothelial NOS•Neither DDAH is active on SDMA•DPT (a minor pathway) acts on allthree analogues•The enzymes are particularly active inkidney

Protein

PRMT (types I and II)

Modified Protein Containing ADMA+ SDMA+

NMA

Hydrolysis

ADMA +SDMA +NMA

Acetylated

Products

α

-ketoacid

products

Citrulline +

Methylamines

DDAH (types I

and II)

Renal

Excretion

PRMT: Protein arginine methyltransferase

ADMA: Asymmetrical dimethylarginineSDMA: Symmetrical dimethylarginine

NMA: N-monomethylarginine

DDAH: Dimethylaminohydrolase

DPT: Dimethylarginine pyruvate transferase

DPT

In slides 18 and 19, results from

Cooke et al (1992) are shown. Theinvestigators fed male rabbits either (a)normal chow (control) or (b) 1%cholesterol diet; or (c) 1% cholesteroldiet supplemented with drinking watercontaining 2.25% L-arginine HCl. After10 weeks of dietary intervention,analyses indicated:

Endothelium dependent relaxation ofthe thoracic aortae elicited byacetylcholine was reduced incholesterol-fed animals and theresponse was significantlyameliorated by L-arginine. L-arginine also significantly reducedthe lesion surface area in thedescending thoracic aorta elicited bycholesterol diets (intima thicknessalso reduced)

0

40 30 20 10

Plaque (% ofTotal Surface

Area)

Cholesterol

Arginine

Cooke, JP, et al. Journal of Clinical Investigation (1992) 90:1168-1172.

•Candipan et al (1996) fed rabbitseither normal chow (controls) or 0.5%cholesterol chow for 10 weeks andthen the cholesterol group receivedeither vehicle or L-arginine (2.25% inwater) (arginine group) for anadditional 13 weeks.