S-Nitroso-glutathione GSNO

Erythrocytes efficiently scavenge GSNO-derived NO, raising doubt about GSNO s potential to exert an anti-thrombotic effect in vivo [128, 129]. Yet de Beider and colleagues demonstrated in healthy male volunteers that GSNO infusions up to 

L-Arginine S(+)-2-Amino-5-[(aminoiminomethyl)amino]pentanoic acid (L-arg) 

As shown in double-blind, placebo-controlled, randomized studies with healthy subjects, both infused [145] and oral [146] L-arg significantly inhibited (by =40%) ADP-induced platelet aggregation in vitro and potentiated platelet cGMP content. The effect, though, was weak the plasma concentration of L-arg required to produce an anti-platelet effect was some 2-fold above normal, steady-state levels, and the oral anti-aggregatory L-arg dose was 4-fold greater than the usual daily L-arg intake in humans. The infused L-arg dose that effectively inhibited platelet activity (30 g total) was hypotensive and increased heart rate, whereas the oral anti-platelet dose (7 g per day over 3 days) did not affect blood pressure, suggestive of oral L-arg platelet selectivity. 

A comprehensive, randomized, placebo-controlled trial of infused bolus L-arg and its enantiomer (D-arg) included healthy subjects, non-insulin dependent diabetics, hypertensive subjects, and normotensives with primary hypercholesterolemia [147]. A blood-pressure drop and an acute inhibition of ADP-induced aggregation in platelet-rich plasma were observed in all subjects after L-arg administration ( 5 g). Both responses to L-arg infusion closely correlated in magnitude, were weaker in noninsulin dependent diabetics and hypercholesterolemics, and declined with increasing age. Notably, D-arg did not elicit any of the L-arg effects, which were reduced by some 70% when superimposed upon ongoing, nonselective NOS inhibition with infused L-N-monomethyl-arginine (L-NMMA). Since D-arg is not a NOS substrate, and L-NMMA is a substrate-competitive NOS inhibitor, the L-arg effects observed in this study were theorized to reflect a rise in vascular NO production by eNOS. In contrast, the inhibition of platelet aggregation observed in vitro after a 5 min L-arg infusion (160 mg total dose) into healthy subjects and patients with angiographic 

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