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Inactivation of nitric oxide synthase isoforms by diaminoguanidine and NG-amino-L-arginine.
- Source :
-
Archives of biochemistry and biophysics [Arch Biochem Biophys] 1996 Jan 15; Vol. 325 (2), pp. 227-34. - Publication Year :
- 1996
-
Abstract
- Diaminoguanidine (DAG) and NG-amino-L-arginine each produced a time- and concentration-dependent inactivation of the citrulline-forming activity of all three NOS isoforms. DAG inactivates both the NADPH-oxidase and the citrulline-forming activities of GH3 pituitary nNOS while NG-amino-L-arginine inactivates only its citrulline-forming activity. The inactivation by DAG of GH3 nNOS NADPH-oxidase and citrulline forming activities is stimulated by (6R)-5,6,7,8-tetrahydrobiopterin (BH4) cofactor, follows pseudo-first-order kinetics and is not substrate saturable. DAG-induced inactivation of the citrulline-forming activity for the iNOS and eNOS isoforms displayed maximal inactivation rates of 0.37 and 0.14 min-1 and Ki values of 385 and 670 microM, respectively. At 1 mM DAG and saturating BH4, half-times of inactivation of 0.7, 8, and 2 min were observed for the nNOS, eNOS, and iNOS isoforms, respectively. NG-Amino-L-arginine-induced inactivation of the citrulline-forming activity of the nNOS, iNOS, and eNOS isoforms displayed maximal inactivation rates of 0.35, 0.26, and 0.53 min-1 and Ki values of 0.3, 3, and 2.5 microM, respectively. The inactivation of the NOS activities by both DAG and NG-amino-L-arginine in preincubations required the presence of oxygen and Ca2+, consistent with an inactivation mechanism that requires active metabolism by NOS. Methylguanidine and 1,1-dimethylguanidine exhibited a reversible inhibition pattern in contrast to all three NOS isoforms. Neither agent exhibited significant isoform selectivity.
- Subjects :
- Animals
Arginine pharmacology
Cattle
Citrulline biosynthesis
In Vitro Techniques
Methylguanidine analogs & derivatives
Methylguanidine pharmacology
Mice
NADH, NADPH Oxidoreductases antagonists & inhibitors
NADPH Oxidases
Oxidation-Reduction
Rats
Arginine analogs & derivatives
Enzyme Inhibitors pharmacology
Guanidines pharmacology
Isoenzymes antagonists & inhibitors
Nitric Oxide Synthase antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0003-9861
- Volume :
- 325
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Archives of biochemistry and biophysics
- Publication Type :
- Academic Journal
- Accession number :
- 8561501
- Full Text :
- https://doi.org/10.1006/abbi.1996.0028