The aim of the present work was to study the effect of 3-mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (CMTI), an efficient aldose reductase inhibitor, on sorbitol accumulation in selected organs of streptozotocin-induced diabetic rats in vivo. In addition, the effect of CMTI on aldose reductase back reaction and on sorbitol dehydrogenase was determined. The model of experimental diabetes in male Wistar rats induced by streptozotocin was used. Experimental diabetes was induced by triple intraperitoneal doses of streptozotocin on three consecutive days. In diabetic rats, significant elevation of sorbitol concentration in the sciatic nerve and eye lenses was recorded. CMTI administered intragastrically (50 mg/kg/day) for five consecutive days significantly inhibited sorbitol accumulation in the sciatic nerve, yet it was without effect in eye lenses of diabetic animals. For aldose reductase back reaction, the substrate affinity of glycerol to aldose reductase was one order lower than that of glyceraldehyde in forward reaction. In addition, the back reaction was much slower, characterized by V(max) value of about 30 times lower than that of the forward reaction. Inhibition of aldose reductase by CMTI was characterized by closely related IC(50) values in submicromolar range for both forward and back reactions. No significant inhibition of the second enzyme of the polyol pathway, sorbitol dehydrogenase, by 100 microM CMTI was recorded (I=0.9+/-2.7 %, n=3). To conclude, the presented results showed the ability of CMTI to affect the polyol pathway in diabetic rats in vivo and represent thus a further step in a complex preclinical evaluation of CMTI as a potential agent for treatment of chronic diabetic complications.
- MeSH
- aldehydreduktasa antagonisté a inhibitory metabolismus MeSH
- experimentální diabetes mellitus chemicky indukované farmakoterapie metabolismus MeSH
- krysa rodu rattus MeSH
- polymery metabolismus MeSH
- potkani Wistar MeSH
- signální transdukce účinky léků MeSH
- sorbitol metabolismus MeSH
- streptozocin MeSH
- sulfhydrylové sloučeniny aplikace a dávkování MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- erytrocyty metabolismus účinky léků MeSH
- experimenty na zvířatech MeSH
- financování organizované MeSH
- glukosa metabolismus MeSH
- indoly metabolismus MeSH
- komplikace diabetu metabolismus MeSH
- kyselina octová metabolismus MeSH
- polymery chemie metabolismus MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- abstrakty MeSH
- Publikační typ
- abstrakt z konference MeSH
- MeSH
- antioxidancia aplikace a dávkování farmakologie MeSH
- experimentální diabetes mellitus enzymologie metabolismus MeSH
- karboliny aplikace a dávkování farmakologie MeSH
- krysa rodu rattus MeSH
- ledviny enzymologie metabolismus MeSH
- sodík metabolismus MeSH
- sodíko-draslíková ATPasa metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- abstrakt z konference MeSH
- MeSH
- albuminurie farmakoterapie MeSH
- antioxidancia farmakologie MeSH
- diabetické nefropatie farmakoterapie MeSH
- experimentální diabetes mellitus farmakoterapie MeSH
- finanční podpora výzkumu jako téma MeSH
- karboliny farmakologie MeSH
- kolagen chemie MeSH
- krysa rodu rattus MeSH
- ledviny metabolismus patologie účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- MeSH
- antioxidancia aplikace a dávkování farmakologie MeSH
- diabetické angiopatie farmakoterapie patofyziologie patologie MeSH
- experimentální diabetes mellitus farmakoterapie patofyziologie patologie MeSH
- karboliny farmakologie MeSH
- krysa rodu rattus MeSH
- pití účinky léků MeSH
- přijímání potravy účinky léků MeSH
- techniky in vitro MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
