Effects of NG-methyl-L-arginine, NG-nitro-L-arginine, and aminoguanidine on constitutive and inducible nitric oxide synthase in rat aorta.
A new selective inhibitor of the inducible nitric oxide synthase in the treatment of pathogenesis characterized by overproduction of nitric oxide may be useful. Therefore, we have examined the effects of two L-arginine analogues, NG-methyl-L-arginine (L-NMA) and NG-nitro-L-arginine (L-NNA), and aminoguanidine (AG) on the constitutive and inducible nitric oxide synthase in rat aorta. L-NNA induced greater contractions to phenylephrine than L-NMA whereas AG had no effect on dose-response curves to this alpha 1-agonist in rat aorta with endothelium. Relaxations to acetylcholine, adenosine triphosphate, and A 23187 were fully abolished by L-NNA, while L-NMA partially inhibited and AG did not affect the relaxations to these three vasodilators. L-NNA, L-NMA, and AG were equipotent in inhibiting the vascular hyporeactivity to phenylephrine induced by endotoxin in rat aortic rings with endothelium; however, the rate of onset of the maximum inhibitory effects of AG was slower than that obtained with L-NNA and L-NMA. L-arginine completely abolished the effects of AG, but only partially reversed the effects of L-NNA and L-NMA in LPS-treated rings. These results suggest that AG selectively inhibits inducible nitric oxide synthase, whereas L-NNA and L-NMA exert their effects on both the constitutive and inducible nitric oxide synthase.
Joly
G A
GA
Department of Genitourinary Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Ayres
M
M
Chelly
F
F
Kilbourn
R G
RG
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000818:Animals; D001011:Aorta / Q000201:enzymology; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004790:Enzyme Induction; D006146:Guanidines / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D051381:Rats; D013329:Structure-Activity Relationship; D019323:omega-N-Methylarginine
D006146:Guanidines; D008070:Lipopolysaccharides; D019335:Nitroarginine; D019323:omega-N-Methylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; C004479:pimagedine