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Prevention of diabetic vascular dysfunction by guanidines. Inhibition of nitric oxide synthase versus advanced glycation end-product formation.
- Source :
-
Diabetes [Diabetes] 1993 Feb; Vol. 42 (2), pp. 221-32. - Publication Year :
- 1993
-
Abstract
- This study was undertaken to compare the ability of two guanidine compounds (aminoguanidine and methylguanidine), with different in vitro effects on NO synthase activity and AGE formation, to inhibit diabetic vascular dysfunction developing early after the onset of diabetes. In rats with STZ-induced diabetes of 5-wk duration, regional vascular [125I]albumin permeation was increased about two- to threefold in ocular tissues, sciatic nerve, and aorta; in general, both guanidine compounds normalized albumin permeation in diabetic rats without affecting it in controls. Methylguanidine was only approximately 7% as effective as aminoguanidine as an inhibitor of AGE formation from L-lysine and G6P; both compounds were poor inhibitors of AR. Methylguanidine was approximately 1-5% as potent as aminoguanidine and L-NMMA as an inhibitor of the cytokine- and endotoxin-inducible isoform of NO synthase. In contrast, the potency of methylguanidine as an inhibitor of the constitutive isoform of NO synthase was comparable to that of aminoguanidine, and both guanidine compounds were much less effective than L-NMMA. These observations suggest a role for a relative or absolute increase in NO production in the pathogenesis of early diabetic vascular dysfunction and raise the possibility that inhibition of diabetic vascular functional changes by aminoguanidine may reflect inhibition of NO synthase activity rather than, or in addition to, prevention of AGE formation.
- Subjects :
- Aldehyde Reductase antagonists & inhibitors
Animals
Arginine analogs & derivatives
Arginine pharmacology
Benzothiazoles
Blood Pressure drug effects
Body Weight drug effects
Capillary Permeability
Citrulline analysis
Diabetes Mellitus, Experimental blood
Diabetic Angiopathies blood
Diabetic Angiopathies physiopathology
Glycation End Products, Advanced analysis
Imidazoles pharmacology
Inositol metabolism
Iodine Radioisotopes
Male
Naphthalenes pharmacology
Nitric Oxide Synthase
Phthalazines pharmacology
Rats
Rats, Sprague-Dawley
Retina drug effects
Retina metabolism
Sciatic Nerve drug effects
Sciatic Nerve metabolism
Serum Albumin, Bovine metabolism
Serum Albumin, Bovine pharmacokinetics
Sorbitol metabolism
Thiazoles pharmacology
Uvea drug effects
Uvea metabolism
omega-N-Methylarginine
Amino Acid Oxidoreductases antagonists & inhibitors
Diabetes Mellitus, Experimental physiopathology
Diabetic Angiopathies prevention & control
Glycation End Products, Advanced metabolism
Guanidines therapeutic use
Imidazolidines
Methylguanidine therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 0012-1797
- Volume :
- 42
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 7678825
- Full Text :
- https://doi.org/10.2337/diab.42.2.221