Enhanced nitric oxide synthesis in uremia: implications for platelet dysfunction and dialysis hypotension.
Nitric oxide (NO), a potent vasodilator which also inhibits platelet adhesion and aggregation, is generated by endothelial cells and platelets from its precursor L-arginine. Since N-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis, normalizes the prolonged bleeding time of uremic rats, it has been suggested that bleeding associated with uremia was due to an excessive NO formation. With the present study we sought to evaluate whether in patients with chronic renal failure--like in uremic rats--defective platelet aggregation were associated with excessive formation of NO and whether uremic plasma promotes NO synthesis by cultured vascular endothelium. Data indicated that plasma L-arginine was higher in uremics than in controls, uremic platelets generated more NO than control platelets, and intraplatelet levels of cGMP (the NO second messenger) were also higher in uremic than in control platelets. Moreover, uremic plasma potently induced NO synthesis by cultured endothelial cells, a phenomenon which was further amplified by adding to uremic plasma endotoxin and interferon gamma. Increased NO biosynthesis may contribute to platelet dysfunction and possibly other manifestations of uremic syndrome, including hemodialysis hypotension.
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
M
M
Noris
A
A
Benigni
P
P
Boccardo
S
S
Aiello
F
F
Gaspari
M
M
Todeschini
M
M
Figliuzzi
G
G
Remuzzi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000097:blood; D001791:Blood Platelet Disorders / Q000209:etiology*; D001792:Blood Platelets / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D007022:Hypotension / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D006435:Renal Dialysis / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014511:Uremia / Q000097:blood* / Q000378:metabolism* / Q000628:therapy
D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D001120:Arginine