Original Contributions L-Arginine Attenuates Platelet Reactivity in Hypercholesterolemic Rabbits
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چکیده
Platelets are capable of producing nitric oxide (NO) through the L-arginine-NO synthase pathway. Acute exposure to supraphysiological concentrations of L-arginine in vitro increases the production of NO by platelets and is associated with an increase in platelet cyclic GMP (cGMP) levels and a reduction in platelet aggregation. The purpose of this study was to determine if chronic oral administration of L-arginine decreases platelet aggregation in hypercholesterolemic animals and to determine if this effect is mediated by the metabolism of L-arginine to NO. Male New Zealand White rabbits were fed normal chow (Con), a 1% cholesterol diet (Choi), or a 1% cholesterol diet supplemented with a sixfold enrichment of dietary L-arginine (Arg) or L-methionine (Met). After 10 weeks, cholesterol levels were equally increased in Choi and Arg animals, whereas plasma arginine levels were A therogenesis is thought to be initiated as a re/ \ sponse to injury of the endothelium. This -Z. A . alteration of endothelial function favors platelet adherence and aggregation to the luminal surface, with the subsequent release of platelet-derived growth factors and vasoactive substances that contribute to the process of atherogenesis. One of the earliest alterations of the endothelium that has been observed in hypercholesterolemic animals and humans is decreased activity of endothelium-derived relaxing factor (EDRF). EDRF is nitric oxide (NO) or a nitroso-containing compound derived from the metabolism of L-arginine by NO synthase. This nitrovasodilator also inhibits platelet adhesion and aggregation via the stimulation of intracellular guanylate cyclase to increase intracellular levels of cyclic GMP (cGMP). NO synthase and guanylate cyclase are also active in platelets, and platelet-derived NO autoregulates aggregation.A reduction in the activity of NO synthase by hypercholesterolemia could therefore lead to increased platelet-vessel wall interaction and enhanced atherogenesis. Recent studies in this laboratory have shown that chronic oral supplementation of the EDRF precursor L-arginine significantly improved NO-dependent vasodilation in hypercholesterolemic animals; this effect was associated with a striking reduction in intimal lesions. To determine if this antiatherogenic effect of L-arginine Received August 13, 1993; revision accepted July 15, 1994. From the Divisions of Cardiovascular Medicine (P.S.T., G.T., A.H.S., J.P.C.) and Hematology (L.L.-K.L.), Stanford University School of Medicine, Stanford, Calif. Correspondence to John P. Cooke, MD, PhD, Division of Cardiovascular Medicine, CVRC, Stanford University School of Medicine, Stanford, CA 94305. O 1994 American Heart Association, Inc. doubled in the Arg group. There was no difference in maximum aggregation initiated by ADP (100 ^mol/L) between washed platelets from Con, Met, and Choi animals, but aggregation of platelets from Arg animals was significantly decreased (/<.05). In aggregating platelets from Arg animals, cGMP levels were significantly higher than the other groups (P<.05). When platelets were incubated ex vivo with the NO synthase inhibitor Af°-monomethyl-L-arginine, the effects of dietary L-arginine were reversed. Chronic dietary supplementation of L-arginine decreases platelet aggregation in hypercholesterolemic rabbits. This effect appears to be due to the metabolism of L-arginine to NO. (Arterioscler Thromb. 1994;14:1529-1533.)
منابع مشابه
L-arginine attenuates platelet reactivity in hypercholesterolemic rabbits.
Platelets are capable of producing nitric oxide (NO) through the L-arginine-NO synthase pathway. Acute exposure to supraphysiological concentrations of L-arginine in vitro increases the production of NO by platelets and is associated with an increase in platelet cyclic GMP (cGMP) levels and a reduction in platelet aggregation. The purpose of this study was to determine if chronic oral administr...
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We hypothesized that normal vascular reactivity could be restored in vessels from hypercholesterolemic animals by exposing them to L-arginine, the precursor of endothelium-derived relaxing factor (EDRF). Basilar arteries were harvested from New Zealand white rabbits fed normal chow or that supplemented with 2% cholesterol for 10 wk. Vessels were cannulated for perfusion at physiologic pressure....
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In hypercholesterolemic rabbits, oral L-arginine (the substrate for endothelium derived nitric oxide) attenuates endothelial dysfunction and atheroma formation, but the effect in hypercholesterolemic humans is unknown. Using high resolution external ultrasound, we studied arterial physiology in 27 hypercholesterolemic subjects aged 29+/-5 (19-40) years, with known endothelial dysfunction and LD...
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تاریخ انتشار 2005