L-arginine attenuates platelet reactivity in hypercholesterolemic rabbits.

Abstract

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. 1 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). 24 EDRF is nitric oxide (NO) or a nitroso-containing compound derived from the metabolism of L-arginine by NO synthase. 58 This nitrovasodilator also inhibits platelet adhesion 9 and aggregation via the stimulation of intracellular guanylate cyclase to increase intracellular levels of cyclic GMP (cGMP). 1011 NO synthase and guanylate cyclase are also active in platelets, and platelet-derived NO autoregulates aggregation. 12 -13 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. 14 To determine if this antiatherogenic effect of L-arginine Received August 13, 1993; revision accepted July 15, 1994 is associated with decreased platelet reactivity and enhancement of platelet-derived NO activity, we tested the hypothesis that (1) dietary L-arginine reduces platelet aggregation and (2) this effect is mediated by the metabolism of L-arginine to NO. Methods AnimalsMale New Zealand White rabbits received one of the following dietary interventions for 10 weeks: normal rabbit chow (Con), rabbit chow enriched with 1% cholesterol (Choi) (ICN Biomedical), or a 1% cholesterol chow supplemented with L-arginine (Arg) added to the drinking water throughout the course of the study. Supplementation with 2.25% L-arginine HO in the drinking water results in a sixfold e...

Effect of Atherosclerosis on Endothelium-Dependent Inhibition of Platelet Activation in Humans

“…[61][62][63][64] Incubation of platelets with L-arginine at concentrations estimated to be produced in vivo in the present study resulted in inhibition of whole blood platelet aggregation to the same extent as during intra-arterial infusion of L-arginine, suggesting that the effect of L-arginine is exerted directly on platelets in the lumen and not via stimulation of the endothelial NO pathway. This direct platelet inhibitory effect of L-arginine appears to be secondary to increased platelet NO activity, 14,65 and human studies that used oral supplementation of L-arginine, which increases plasma L-arginine levels by up to 2-fold, have also shown inhibition of platelet aggregation in normal individuals and patients with hypercholesterolemia.…”

Asymmetric Dimethylarginine (ADMA): A Novel Risk Factor for Endothelial Dysfunction

“…In HC rabbits, long-term oral administration of L-arginine restores endothelial elaboration of NO, reduces endothelial adhesiveness for monocytes, inhibits platelet aggregation, retards atherogenesis, and even induces regression of preexisting lesions. 12,13,[15][16][17][18][19][20][21][22]44 By contrast, longterm antagonism of NO synthase accelerates atherogenesis in animal models. 13,14,16,45 Recently, it has been observed that ADMA levels are correlated with the severity of disease in patients with peripheral arterial disease.…”

Endogenous Nitric Oxide Synthase Inhibitor

“…It is well known that L-arginine supplementation enhances the synthesis of endothelium-derived NO, 30 restores endothelial vasodilator function, [32][33][34] inhibits platelet aggregation 35,36 and cell adhesion, 20,[37][38][39][40] and attenuates atherosclerosis [41][42][43][44][45] in hypercholesterolemic animals and in humans. It is possible that L-arginine exerts these beneficial effects by reversing the action of the competitive inhibition by ADMA.…”