ENHANCED NITRIC-OXIDE SYNTHESIS IN UREMIA - IMPLICATIONS FOR PLATELETDYSFUNCTION AND DIALYSIS HYPOTENSION

Nitric oxide (NO), a potent vasodilator which also inhibits platelet a dhesion and aggregation, is generated by endothelial cells and platele ts from its precursor L-arginine. Since N-monomethyl-L-arginine (L-NMM A), an inhibitor of NO synthesis, normalizes the prolonged bleeding ti me of uremic rats, it has been suggested that bleeding associated with uremia was due to an excessive NO formation. With the present study w e sought to evaluate whether in patients with chronic renal failure-li ke in uremic rats-defective platelet aggregation were associated with excessive formation of NO and whether uremic plasma promotes NO synthe sis by cultured vascular endothelium. Data indicated that plasma L-arg inine was higher in uremics than in controls, uremic platelets generat ed more NO than control platelets, and intraplatelet levels of cGMP (t he NO second messenger) were also higher in uremic than in control pla telets. Moreover, uremic plasma potently induced NO synthesis by cultu red endothelial cells, a phenomenon which was further amplified by add ing to uremic plasma endotoxin and interferon gamma. Increased NO bios ynthesis may contribute to platelet dysfunction and possibly other man ifestations of uremic syndrome, including hemodialysis hypotension.