Amidines are potent inhibitors of nitric oxide synthases: preferential inhibition of the inducible isoform.
We evaluated the ability of simple alkyl amidines to inhibit the activity of the inducible isoform of nitric oxide (NO) synthase in vitro. In immunostimulated J774 macrophages, 2-iminopiperidine (EC50 = 10 microM) and butyramidine (EC50 = 60 microM) were more potent than NG-methyl-L-arginine (EC50 = 70 microM) in inhibiting nitrite formation. The five amidines tested for their ability to inhibit the conversion of L-arginine to L-citrulline by bovine endothelial cell homogenates (a source of the constitutive, endothelial NO synthase isoform) were less effective than NG-nitro-L-arginine or NG-methyl-L-arginine. The rank-order of the potencies of the amidines against the endothelial NO synthase was, in general, similar to the rank-order of the pressor effects of these agents in anesthetized rats. Thus, certain amidines are potent inhibitors of NO synthase, and are more selective towards the inducible NO synthase than the commonly used L-arginine based NO synthase inhibitors.
Southan
G J
GJ
Children's Hospital Medical Center, Division of Critical Care, Cincinnali, OH 45229, USA.
Szabó
C
C
Connor
M P
MP
Salzman
A L
AL
Thiemermann
C
C
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019335:Nitroarginine; D051381:Rats; D017208:Rats, Wistar; D019323:omega-N-Methylarginine
D000578:Amidines; D007527:Isoenzymes; D019335:Nitroarginine; D019323:omega-N-Methylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase