Dietary L-Arginine Supplementation Normalizes Platelet Aggregation in Hypercholesterolemic Humans

Objectives. The present study was designed to test the hypothesis that long-term dietary supplementation with the nitric oxide precursor image-arginine would enhance vascular or platelet-derived nitric oxide activity, or both, and thereby inhibit platelet reactivity in hypercholesterolemic humans. Background. We have shown that reduced vascular activity of nitric oxide in hypercholesterolemic rabbits can be restored by image-arginine supplementation. The improvement in nitric oxide activity is associated with an inhibition of platelet aggregation ex vivo. This effect is most likely due to increased elaboration of endothelium- or platelet-derived nitric oxide, or both, because the inhibition of platelet reactivity was associated with elevation of intraplatelet cyclic guanosine monophosphate and was reversed by the nitric oxide synthase antagonist N-methyl-arginine. Methods. In double-blinded, randomized, placebo-controlled trial, hypercholesterolemic patients were assigned to image-arginine hydrochloride, 8.4 g/day orally, or placebo for 2 weeks. Platelet-rich plasm was obtained for aggregometry induced by collagen (1 to 10 μg/ml) at four points: baseline, after 2 weeks of treatment, after 2-week washout and after long-term washout of 16 weeks on average. Aggregation was quantified by light transmittance and expressed as percent transmittance observed with platelet-poor plasma. Results. Compared with normocholesterolemic control subjects, platelets from hypercholesterolemic subjects stimulated with 5 μg/ml of collagen showed increased aggregability (68.6% in hypercholesterolemic patients vs. 54.5% in normocholesterolemic control subjects, p ≤ 0.02). After 2 weeks of treatment with image-arginine (but not placebo), platelet reactivity was modestly reduced; this effect persisted for 2 weeks after discontinuation of arginine (52.6% in arginine-treated patients vs. 65.1% in normocholesterolemic control subjects, p = 0.07). After 18 weeks (i.e., 16 weeks after discontinuing arginine treatment), the platelets of hypercholesterolemic patients once again became hyperaggregable, and the extent of platelet aggregation was significantly increased compared with the 4-week point (73.6% after vs. 52.6% during arginine treatment, p < 0.01). No significant change in platelet reactivity was seen in placebo-treated hypercholesterolemic patients throughout the study. image-Arginine treatment was well tolerated without side effects. Conclusions. This double-blinded, placebo-controlled study demonstrates that dietary supplementation with image-arginine can modestly attenuate the increased platelet reactivity seen in hypercholesterolemic patients. The dat are consistent with our previous studies in hypercholesterolemic animals, demonstrating that image-arginine restores endogenous nitric oxide activity and inhibits platelet aggregation. Enhancement of endogenous nitric oxide activity is potential novel therapeutic strategy worthy of further study.