CHRONIC DIETARY SUPPLEMENTATION WITH L-ARGININE INHIBITS PLATELET-AGGREGATION AND THROMBOXANE A(2) SYNTHESIS IN HYPERCHOLESTEROLEMIC RABBITS IN-VIVO

Objectives: L-arginine exerts anti-atherosclerotic effects in hypercho lesterolaemic rabbits via modulating endogenous NO production. We inve stigated whether L-arginine inhibits thromboxane formation in vivo and platelet aggregation ex vivo in this animal model. Methods: The urina ry excretion rates of 2,3-dinor-6-keto-PGF(1 alpha). (major urinary me tabolite of PGI(2)) and 2,3-dinor-TXB2, (major urinary metabolite of t hromboxane A(2)) were used as indicators of platelet-endothelial cell interactions in vivo. Rabbits were fed 1% cholesterol (Cholesterol gro up, N = 8), 1% cholesterol plus 2,25% L-arginine (Cholesterol + L-argi nine, N = 8), or normal rabbit chow(Control, N = 4) for 12 weeks. Urin e samples were collected in weekly intervals. At the end of the study period platelet aggregation ex vivo and endothelium-dependent and -ind ependent vascular function of isolated aortic rings in vitro was asses sed. Results: Urinary 2,3-dinor-TXB2 excretion significantly increased in the cholesterol group (p < 0.05), and endogenous NO formation (mea sured as urinary nitrate excretion) decreased (p < 0.05). Both paramet ers were significantly correlated with each other (R = 0.48, p < 0.01) . L-arginine partly restored urinary nitrate excretion and significant ly reduced TXA(2), production to values even below those in the contro l group (p < 0.001). Urinary 2,3-dinor-6-keto-PGF(1 alpha) excretion i ncreased 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-PGF(1 alpha) excretion was attenuated by L-arginine. Platelet aggregation was significantly enhanced in cholesterol-fed ra bbits and attenuated by dietary L-arginine. L-arginine also improved t he impaired endothelium-dependent relaxations to ADP, and normalized t he vasoconstrictor effects of 5-HT in isolated aortic rings. Conclusio ns: Cholesterol-feeding enhances platelet aggregation and TXA(2) forma tion, and stimulates platelet-endothelial cell interaction in rabbits. These effects are probably due to impaired NO elaboration. as indicat ed by decreased urinary nitrate excretion. Chronic dietary supplementa tion with L-arginine elevates systemic NO elaboration and significantl y increases the PGI(2)/TXA(2) ratio. It thus beneficially influences t he homeostasis between vasodilator and vasoconstrictor prostanoids in vivo. (C) 1998 Elsevier Science B.V.