Interactions between the sorbitol pathway, non-enzymatic glycation, and diabetic vascular dysfunction.

BACKGROUND Many lines of evidence attest to a multifactorial pathogenesis of diabetic complications in humans and in animal models of diabetes. Increased sorbitol pathway metabolism and non-enzymatic glycation products have been implicated by many investigators in the pathogenesis of vascular and neural dysfunction as well as early vascular structural changes in animal models of diabetes. The present studies were undertaken to assess the mechanisms that mediate vascular dysfunction associated with these biochemical imbalances. METHODS Three different animal models of diabetes were used: (1) rats with diabetes induced by injection of streptozotocin; (2) non-diabetic rats with acute hyperglycaemia of 5 h duration induced by i.v. glucose infusion at a rate sufficient to produce plasma glucose levels comparable to those in diabetic rats; and (3) the skin chamber granulation tissue model in which vessels in the chamber are exposed to buffer containing 5 or 30 mM glucose +/- pharmacological agents or 0.1 microM glycated rat serum albumin +/- pharmacological agents. Vascular function was assessed by injection of 11.3 microns 46Sc microspheres for quantification of blood flow and by injection of [125I] and [131I]bovine serum albumin for quantification of vascular albumin permeation. RESULTS Vascular dysfunction induced by elevated glucose levels (increased blood flow and increased albumin permeation) in all three models was prevented by inhibitors of sorbitol pathway metabolism, inhibitors of nitric oxide synthesis and inhibitors of prostaglandin synthesis. In the skin chamber model vascular dysfunction induced by elevated glucose levels and by glycated rat serum albumin was prevented by superoxide dismutase, probucol and inhibitors of nitric oxide synthase. CONCLUSIONS These observations suggest that vascular dysfunction induced by increased sorbitol pathway metabolism (caused by elevated glucose levels) and by products of non-enzymatic glycation (at normal glucose levels) is mediated by a common final pathway consistent with a scenario in which: increases superoxide production-->increases intracellular calcium levels-->increases nitric oxide synthesis-->increases blood flow and increases vascular permeability.