Chronic dietary supplementation with L-arginine inhibits platelet aggregation and thromboxane A2 synthesis in hypercholesterolaemic rabbits in vivo.
OBJECTIVE
L-arginine exerts anti-atherosclerotic effects in hypercholesterolaemic rabbits via modulating endogenous NO production. We investigated whether L-arginine inhibits thromboxane formation in vivo and platelet aggregation ex vivo in this animal model.


METHODS
The urinary excretion rates of 2,3-dinor-6-keto-PGF1 alpha (major urinary metabolite of PGI2) and 2,3-dinor-TXB2 (major urinary metabolite of thromboxane A2) were used as indicators of platelet-endothelial cell interactions in vivo. Rabbits were fed 1% cholesterol (Cholesterol group, N = 8), 1% cholesterol plus 2.25% L-arginine (Cholesterol + L-arginine, N = 8), or normal rabbit chow (Control, N = 4) for 12 weeks. Urine samples were collected in weekly intervals. At the end of the study period platelet aggregation ex vivo and endothelium-dependent and -independent vascular function of isolated aortic rings in vitro was assessed.


RESULTS
Urinary 2,3-dinor-TXB2 excretion significantly increased in the cholesterol group (p < 0.05), and endogenous NO formation (measured as urinary nitrate excretion) decreased (p < 0.05). Both parameters were significantly correlated with each other (R = 0.48, p < 0.01). L-arginine partly restored urinary nitrate excretion and significantly reduced TXA2 production to values even below those in the control group (p < 0.001). Urinary 2,3-dinor-6-keto-PGF1 alpha excretion increased in early hypercholesterolaemia and returned to control values in the second half of the study period. The early increase in urinary 2,3-dinor-6-keto-PGF1 alpha excretion was attenuated by L-arginine. Platelet aggregation was significantly enhanced in cholesterol-fed rabbits and attenuated by dietary L-arginine. L-arginine also improved the impaired endothelium-dependent relaxations to ADP, and normalized the vasoconstrictor effects of 5-HT in isolated aortic rings.


CONCLUSIONS
Cholesterol-feeding enhances platelet aggregation and TXA2 formation, and stimulates platelet-endothelial cell interaction in rabbits. These effects are probably due to impaired NO elaboration, as indicated by decreased urinary nitrate excretion. Chronic dietary supplementation with L-arginine elevates systemic NO elaboration and significantly increases the PGI2/TXA2 ratio. It thus beneficially influences the homeostasis between vasodilator and vasoconstrictor prostanoids in vivo.
Bode-Böger
S M
SM
Institute of Clinical Pharmacology, Hannover Medical School, Germany.
Böger
R H
RH
Kienke
S
S
Böhme
M
M
Phivthong-ngam
L
L
Tsikas
D
D
Frölich
J C
JC
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001120:Arginine / Q000008:administration & dosage* / Q000097:blood; D015415:Biomarkers / Q000652:urine; D003404:Creatinine / Q000652:urine; D004032:Diet; D004730:Endothelium, Vascular / Q000187:drug effects; D011464:Epoprostenol / Q000652:urine; D008401:Gas Chromatography-Mass Spectrometry; D006937:Hypercholesterolemia / Q000097:blood / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009566:Nitrates / Q000652:urine; D009599:Nitroprusside / Q000494:pharmacology; D010974:Platelet Aggregation; D011817:Rabbits; D013928:Thromboxane A2 / Q000096:biosynthesis*; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine; D014665:Vasodilator Agents / Q000494:pharmacology
D015415:Biomarkers; D009566:Nitrates; D014665:Vasodilator Agents; D009599:Nitroprusside; D013929:Thromboxane B2; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; C028965:2,3-dinor-thromboxane B2; D001120:Arginine; D003404:Creatinine; D011464:Epoprostenol