Effects of guanidino and uremic compounds on nitric oxide pathways.
Aminoguanidine, NG-monomethyl-L-arginine (L-NMMA), NGNGdimethyl-L-arginine (asymmetric dimethylarginine; ADMA), creatinine, guanidinosuccinic acid, guanidinoproprionic acid and methylguanidine were added to cultures of activated murine macrophages. Only aminoguanidine, ADMA, L-NMMA and methylguanidine inhibited nitrite production in a dose-dependent manner. In the presence of 100 microM arginine, nitrite production was inhibited by 31.8 +/- 7.1% by ADMA (100 microM; P < 0.01) but the same dose of methylguanidine was without effect. A higher dose of methylguanidine (1000 microM) inhibited nitrite production by 47.6 +/- 5.6% (P < 0.001). The effects of these compounds were also tested on relaxation of human saphenous veins. L-NMMA and ADMA inhibited endothelium-dependent relaxations (EC50 = 4.7 +/- 1.1 microM and 17.9 +/- 4.9 microM, respectively); methylguanidine caused endothelium-independent contractions and reversed the relaxations to bradykinin and sodium nitroprusside (EC50 > 100 microM); aminoguanidine was without effect. The results of this study suggest that of the guanidino compounds which accumulate in renal failure, only ADMA is a potent inhibitor of nitric oxide (NO) synthesis. Methylguanidine is a weak inhibitor of nitric oxide synthesis, whereas the closely related compound aminoguanidine appears to inhibit selectively the inducible isoform of nitric oxide synthase and has no effect on constitutive NO synthase in human veins.
MacAllister
R J
RJ
Department of Pharmacology and Clinical Pharmacology, St. George's Hospital Medical School, London, England, United Kingdom.
Whitley
G S
GS
Vallance
P
P
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D009126:Muscle Relaxation; D009131:Muscle, Smooth, Vascular; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase; D012501:Saphenous Vein; D019323:omega-N-Methylarginine
D006146:Guanidines; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases