INTERACTIONS BETWEEN THE SORBITOL PATHWAY, NONENZYMATIC GLYCATION, AND DIABETIC VASCULAR DYSFUNCTION

Background. Many lines of evidence attest to a multifactorial pathogen esis of diabetic complications in humans and in animal models of diabe tes. Increased sorbitol pathway metabolism and non-enzymatic glycation products have been implicated by many investigators in the pathogenes is of vascular and neural dysfunction as well as early vascular struct ural changes in animal models of diabetes. The present studies were un dertaken to assess the mechanisms that mediate vascular dysfunction as sociated with these biochemical imbalances. Methods. Three different a nimal models of diabetes were used: (1) rats with diabetes induced by injection of streptozotocin; (2) non-diabetic rats with acute hypergly caemia of 5 h duration induced by i.v. glucose infusion at a rate suff icient to produce plasma glucose levels comparable to those in diabeti c rats; and (3) the skin chamber granulation tissue model in which ves sels in the chamber are exposed to buffer containing 5 or 30 mM glucos e+/-pharmacological agents or 0.1 mu M glycated rat serum albumin+/-ph armacological agents. Vascular function was assessed by injection of 1 1.3 mu m Sc-46 microspheres for quantification of blood now and by inj ection of [I-125] and [I-131]bovine serum albumin for quantification o f vascular albumin permeation. Results. Vascular dysfunction induced b y elevated glucose levels (increased blood flow and increased albumin permeation) in all three models was prevented by inhibitors of sorbito l pathway metabolism. inhibitors of nitric oxide synthesis and inhibit ors of prostaglandin synthesis. In the skin chamber model vascular dys function 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 tha t vascular dysfunction induced by increased sorbitol pathway metabolis m (caused by elevated glucose levels) and by products of non-enzymatic glycation (al normal glucose levels) is mediated by a common final pa thway consistent with a scenario in which: T superoxide production --> up arrow intracellular calcium levels -->up arrow nitric oxide synthes is -->up arrow blood flow and up arrow vascular permeability.