sorbinil and pimagedine

Topics: Aldehyde Reductase; Antioxidants; Clinical Trials as Topic; Cyclooxygenase Inhibitors; Diabetic Retinopathy; Glycation End Products, Advanced; Growth Hormone; Guanidines; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Imidazolidines; Indoles; Maleimides; Octreotide; Oxygen Inhalation Therapy; Platelet Aggregation Inhibitors; Protein Kinase C; Pyrroles; Thiamine; Vascular Endothelial Growth Factor A

Previously we have demonstrated that diabetes causes impairment in vascular function of epineurial vessels, which precedes the slowing of motor nerve conduction velocity. Treatment of diabetic rats with aldose reductase inhibitors, aminoguanidine or myo-inositol supplementation have been shown to improve motor nerve conduction velocity and/or decreased endoneurial blood flow. However, the effect these treatments have on vascular reactivity of epineurial vessels of the sciatic nerve is unknown. In these studies we examined the effect of treating streptozotocin-induced rats with sorbinil, aminoguanidine or myo-inositol on motor nerve conduction velocity, endoneurial blood flow and endothelium-dependent vascular relaxation of arterioles that provide circulation to the region of the sciatic nerve. Treating diabetic rats with sorbinil, aminoguanidine or myo-inositol improved the reduction of endoneurial blood flow and motor nerve conduction velocity. However, only sorbinil treatment significantly improved the diabetes-induced impairment of acetylcholine-mediated vasodilation of epineurial vessels of the sciatic nerve. All three treatments were efficacious in preventing the appropriate metabolic derangements associated with either activation of the polyol pathway or increased nonenzymatic glycation. In addition, sorbinil was shown to prevent the diabetes-induced decrease in lens glutathione level. However, other markers of oxidative stress were not vividly improved by these treatments. These studies suggest that sorbinil treatment may be more effective in preventing neural dysfunction in diabetes than either aminoguanidine or myo-inositol.

Topics: Aldehyde Reductase; Animals; Arginine; Arterioles; Diabetes Mellitus, Experimental; Enzyme Inhibitors; Guanidines; Imidazoles; Imidazolidines; Inositol; Lysine; Male; Neural Conduction; Rats; Rats, Sprague-Dawley; Retina; Sciatic Nerve; Sodium-Potassium-Exchanging ATPase; Superoxides

In the present study, we examined the pattern of Evan's blue (EB) extravasation over time and we verified the effect of two inhibitors of aldose reductase (sorbinil and ARI 509) as well as aminoguanidine, which modulate nitric oxide (NO) production, on streptozotocin-induced capillary extravasation abnormalities in the upper bronchi, heart, kidney, duodenum, pancreas, skeletal muscle and skin. Albumin extravasation was measured using the EB technique (20 mg/kg). On the third day, a transient decrease in EB leakage was observed in the lung (-49%), heart (-29%) and skeletal muscle (-64%). These early changes in EB were transient, and values returned to normal there after. Later on, EB extravasation was significantly enhanced in the skin (+358, +680, +580, +525 and +365, respectively, at 2, 4, 5, 6 and 7 weeks of diabetes), the duodenum (+101, +160, +92, +124 and +76%), the upper bronchus (+70, +113, +70, +41 and +25%) and the pancreas (+43, +102, +46, +15 and +78%). In the kidney, the increase of EB extravasation was significant at 2 weeks (26%), and from 5 to 7 weeks (+12, +22, +36%). The chronic treatment of diabetic rats with aminoguanidine normalized capillary permeability in most tissues, suggesting that NO is involved in the development of endothelium dysfunction in this streptozotocin-induced diabetic model. Treatment with aldose reductase inhibitors selectively normalized EB extravasation in the kidney.

Topics: Aldehyde Reductase; Animals; Capillary Permeability; Coloring Agents; Diabetes Mellitus, Experimental; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Evans Blue; Female; Guanidines; Imidazoles; Imidazolidines; Nitric Oxide; Rats; Rats, Sprague-Dawley; Serum Albumin; Sorbitol

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.

Topics: Aldehyde Reductase; Amino Acid Oxidoreductases; Animals; Arginine; Benzothiazoles; Blood Pressure; Body Weight; Capillary Permeability; Citrulline; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Glycation End Products, Advanced; Guanidines; Imidazoles; Imidazolidines; Inositol; Iodine Radioisotopes; Male; Methylguanidine; Naphthalenes; Nitric Oxide Synthase; omega-N-Methylarginine; Phthalazines; Rats; Rats, Sprague-Dawley; Retina; Sciatic Nerve; Serum Albumin, Bovine; Sorbitol; Thiazoles; Uvea