In recent studies we have demonstrated a marked increase in albumin permeation of new vessels formed by angiogenesis (in subcutaneous tissue) in the diabetic milieu. Likewise, lysyl oxidase-mediated collagen cross-linking is markedly increased in the scar tissue associated with angiogenesis. The present studies were undertaken to determine whether sorbinil, a chemical inhibitor of aldose reductase that has been shown to prevent and reverse diabetic cataracts and neuropathy, also could prevent the vascular permeability and collagen cross-linking changes in this model. Vascular permeation by 125I-BSA, collagen cross-linking, and tissue levels of sorbitol, myo-inositol, and scyllo-inositol were assessed in male Sprague-Dawley rats 3 wk after injection of streptozocin and induction of angiogenesis and collagen synthesis in polyester fabric implanted subcutaneously.
Sorbinil (∼25 mg/kg/day) added to the diet of diabetic rats reduced the diabetes-induced increases in albumin permeation by 80%, completely prevented diabetes-induced changes in tissue levels of sorbitol and myo-inositol, and markedly reduced diabetes-induced changes in tissue levels of scyllo-inositol. In contrast, sorbinil had no effect on plasma glucose levels or collagen solubility (an index of collagen cross-linking). These observations indicate that increased vascular permeability associated with diabetes is linked to imbalancesin sorbitol/inositol metabolism. These findings also indicate that (1) diabetes-induced increases in vascular permeability and in collagen cross-linking are independent phenomena and (2) diabetes-induced increases in vascular permeability are largely preventable by treatment with an aldose reductase inhibitor in the face of high plasma glucose levels.