Diabetes-induced increases in vascular permeability and changes in granulation tissue levels of sorbitol, myo-inositol, chiro-inositol, and scyllo-inositol are prevented by sorbinil.
In a recently developed animal model, we investigated the pathogenesis of diabetic vascular disease and demonstrated that 125I-albumin permeation is markedly increased in new "granulation tissue" vessels formed in subcutaneous tissue after the onset of diabetes. The studies described in this report were undertaken to examine the effects of an aldose reductase inhibitor on diabetes-induced increases in vascular permeability in this animal model. 125I-albumin permeation was assessed 3 weeks after the subcutaneous implantation of sterile preweighed polyester fabric (to stimulate angiogenesis) in diabetic male Sprague-Dawley rats, in controls, and in diabetic rats given sorbinil approximately 12 or approximately 25 mg/kg/d mixed in ground rat chow. Sorbinil administration prevented the diabetes-induced increase in vascular permeability by approximately 60% at the lower dose and by approximately 80% at the higher dose without affecting body weight or plasma glucose levels. Diabetes-induced changes in tissue levels of sorbitol, myo-inositol, scyllo-inositol, and chiro-inositol were also prevented by the high dose of sorbinil (data were not obtained for the lower dose). These observations are consistent with evidence linking diabetic cataracts and neuropathy to imbalances in sorbitol/inositol metabolism and support the hypothesis that diabetic vascular disease as well as neuropathy and cataracts are mediated by excess metabolism of glucose through the polyol pathway. Furthermore, these observations suggest that increased vascular permeability associated with diabetic microangiopathy in humans may be prevented by inhibitors of aldose reductase without the need to normalize blood glucose levels.
D000293:Adolescent; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000378:metabolism; D006097:Granulation Tissue / Q000032:analysis* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D048289:Imidazolidines; D007294:Inositol / Q000032:analysis*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013012:Sorbitol / Q000032:analysis*; D013237:Stereoisomerism
D007093:Imidazoles; D048289:Imidazolidines; C009217:scyllitol; D007294:Inositol; D013012:Sorbitol; C026411:sorbinil