DIETARY L-ARGININE SUPPLEMENTATION NORMALIZES PLATELET-AGGREGATION INHYPERCHOLESTEROLEMIC HUMANS

Objectives. The present study was designed to test the hypothesis that long-term dietary supplementation with the nitric oxide precursor L-a rginine would enhance vascular or platelet-derived nitric oxide activi ty, or both, and thereby inhibit platelet reactivity in hypercholester olemic humans. Background. We have shown that reduced vascular activit y of nitric oxide in hypercholesterolemic rabbits can be restored by L -arginine supplementation. The improvement in nitric oxide activity is associated with an inhibition of platelet aggregation ex vivo. This e ffect is most likely due to increased elaboration of endothelium- or p latelet-derived nitric oxide, or both, because the inhibition of plate let reactivity was associated with elevation of intraplatelet cyclic g uanosine monophosphate and was reversed by the nitric oxide synthase a ntagonist N-methyl-arginine. Methods. In a double-blinded, randomized, placebo-controlled trial, hypercholesterolemic patients were assigned to L-arginine hydrochloride, 8.4 g/day orally, or placebo for 2 weeks . Platelet-rich plasma was obtained for aggregometry induced by collag en (1 to 10 mu g/ml) at four points: baseline, after 2 weeks of treatm ent, after a 2-week washout and after a long-term washout of 16 weeks on average. Aggregation was quantified by light transmittance and expr essed as a percent transmittance observed with platelet-poor plasma. R esults. Compared with normocholesterolemic control subjects, platelets from hypercholesterolemic subjects stimulated with 5 mu g/ml of colla gen showed increased aggregability (68.6% in hypercholesterolemic pati ents vs. 54.5% in normocholesterolemic control subjects, p less than o r equal to 0.02). After 2 weeks of treatment with L-arginine (but not placebo), platelet reactivity was modestly reduced; this effect persis ted for 2 weeks after discontinuation of arginine (52.6% in arginine-t reated patients vs. 65.1% in normocholesterolemic control subjects, p = 0.07). After 18 weeks (i.e., 16 weeks after discontinuing arginine t reatment), the platelets of hypercholesterolemic patients once again b ecame hyperaggregable, and the extent of platelet aggregation was sign ificantly increased compared with the 4-week point (73.6% after vs. 52 .6% during arginine treatment, p < 0.01). No significant change in pla telet reactivity was seen in placebo-treated hypercholesterolemic pati ents throughout the study. L-Arginine treatment was well tolerated wit hout side effects. Conclusions. This double-blinded, placebo-controlle d study demonstrates that dietary supplementation with L-arginine can modestly attenuate the increased platelet reactivity seen in hyperchol esterolemic patients. The data are consistent with our previous studie s in hypercholesterolemic animals, demonstrating that L-arginine resto res endogenous nitric oxide activity and inhibits platelet aggregation . Enhancement of endogenous nitric oxide activity is a potential novel therapeutic strategy worthy of further study. (C) 1997 by the America n College of Cardiology.