The purpose of this study was to determine if chronic administration of L-arginine, the precursor of endothelium-derived relaxing factor (EDRF), normalizes endothelium-dependent relaxation and decreases atherosclerosis in hypercholesterolemic animals. Male rabbits were fed (a) normal rabbit chow; (b) 1% cholesterol diet; or (c) 1% cholesterol diet supplemented by 2.25% L-arginine HCI in drinking water. Arginine supplementation doubled plasma arginine levels without affecting serum cholesterol values. After 10 wk, the thoracic aorta was harvested for studies of vascular reactivity and histomorphometry.Endothelium-dependent relaxations (to acetylcholine and calcium ionophore A23187) were significantly impaired in thoracic aortae from animals fed a 1% cholesterol diet. By contrast, vessels from hypercholesterolemic animals receiving Larginine supplementation exhibited significantly improved endothelium-dependent relaxations. Responses to norepinephrine or nitroglycerin were not affected by either dietary intervention. Histomorphometric analysis revealed a reduction in lesion surface area and intimal thickness in thoracic aortae from arginine-supplemented animals compared to those from untreated hypercholesterolemic rabbits. This is the first study to demonstrate that supplementation of dietary L-arginine, the EDRF precursor, improves endothelium-dependent vasorelaxation. More importantly, we have shown that this improvement in EDRF activity is associated with a reduction in atherogenesis. (J. Clin. Invest. 1992.

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...

Dietary supplements of L-arginine prevent intimal thickening in the coronary arteries of hypercholesterolemic rabbits. This antiatherogenic effect is not due to an alteration in plasma total cholesterol, HDL cholesterol or caloric or nitrogen balance. The data are consistent with the hypothesis that nitric oxide has antiatherogenic properties.

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Seven hundred ten high speed rotational atherectomy (HSRA) procedures were performed in a single consecutive series of 656 patients. Stand alone HSRA was performed in 253 patients (35%). HSRA with adjunctive low pressure (< or = 2 ATM) balloon angioplasty (LP BA) was performed in 221 patients (31%), and HSRA with adjunctive high pressure (> or = 4 ATM) balloon angioplasty (HP BA) was performed in 236 patients (34%). Prognostically unfavorable Type B2 and C lesions dominated the study group (74.7%). Procedural success rate was 96%. Emergency coronary artery bypass surgery was performed in 1.4% of cases, Q wave myocardial infarction occurred in 3.4% and death, related to procedure, was consequent in 0.5% of cases. Incidence of flow limiting dissections was 3.1%, distal spasm was 5.3%, and "no reflow" phenomenon was 1.8%. The recent technique modifications included continuous advancer/guiding catheter infusion of the nitroglycerin-verapamil mixture, limitation of duration of lesion engagement by the burr, stepwise increase in the burr size, decrease of rotational speed, and strict control of rpm drop during lesion ablation. Evolution of the interventional technique involved trends towards decrease of the use of HP BA in conjunction with steady increase in the percentage of SA and LP BA procedures over time. These technique changes resulted in complete absence of "no reflow" in 1994, as well as a generalized decrease in overall coronary vascular reactivity from all burr passes.