Increased Vascular Permeability in Spontaneously Diabetic BB/W Rats and in Rats With Mild Versus Severe Streptozocin-Induced Diabetes: Prevention by Aldose Reductase Inhibitors and Castration

Abstract

125I-labeled albumin permeation (IAP) has been assessed in various tissues in spontaneously diabetic insulin-dependent female BB/W rats and in male Sprague-Dawley rats with severe or mild forms of streptozocin-induced diabetes (SS-D and MS-D, respectively). In BB/W diabetic rats and in rats with SS-D, indices of IAP were significantly increased in tissues and vessels predisposed to diabetic vascular disease in humans, including the eyes (anterior uvea, posterior uvea, and retina), sciatic nerve, aorta, kidney, and new vessels formed after induction of diabetes. No evidence of increased IAP was observed in heart, brain, testes, or skeletal muscle in BB/W or SS-D rats. In MS-D rats, indices of IAP were increased only in the kidney and in new vessels formed after the onset of diabetes. Marked tissue differences were observed in the effects of two structurally different aldose reductase inhibitors (sorbinil and tolrestat) and of castration on diabetes-induced increases in IAP and in tissue levels of polyols in SS-D rats. Both aldose reductase inhibitors and castration completely prevented diabetes-induced increases in IAP in new vessels and in sciatic nerve in BB/W and SS-D rats. Both aldose reductase inhibitors also markedly decreased IAP in the anterior uvea (approximately 85%), posterior uvea (approximately 65-75%), retina (approximately 65-70%), and kidney (approximately 70-100%); castration reduced IAP in the anterior uvea (approximately 55%), kidney (approximately 50%), and retina (approximately 30%) but had no effect on the posterior uvea. The diabetes-induced increases in IAP in the aorta were reduced only slightly (approximately 20%) by aldose reductase inhibitors and castration.(ABSTRACT TRUNCATED AT 250 WORDS)

Electron microscopic immunocytochemical demonstration of blood-retinal barrier breakdown in human diabetics and its association with aldose reductase in retinal vascular endothelium and retinal pigment epithelium

“…Increased AR expression in the cells that comprise the BRB (RVE and RPE) in diabetics supports the hypothesis that AR activity may contribute to the complications of diabetic retinopathy in humans, including BRB breakdown, as has been shown in experimental models (Frank et at., 1983;Robison et at., 1983;Cunha-Vaz eta]., 1985;Lightman et at., 1987;Williamson et al, 1987;Robison el al., 1989;Kador el at., 1990a, b;Vinores et a]., 1990b, c). Aldose reductase synthesis and its mRNA induction are osmotically regulated in kidney (Smardo el al., 1992) and AR may be similarly induced in diabetic retina as a result of elevated serum glucose levels.…”

“…Diabetic and galactosaemic rats develop many complications similar to human diabetics, including BRB failure (Jones et al, 1979;Krupin et al, 1979;Ishibashi et al, 1980;Tso et aI., 1980;Jones et al, 1982;Blair et al, 1984;Vine et aL, 1984;Caldwell et al, 1985;Lightman et al, 1987;Williamson et al, 1987). Based upon electron-microscopic immunocytochemical staining for albumin to determine the method of extravasation in the retinas of these experimental animals, the nature of the BRB breakdown appears to be primarily due to increased focal permeability of the RVE and RPE cells, allowing serum proteins to transgress the barrier and infiltrate the retina (Vinores et aI., 1990b).…”

“…AR inhibitors can largely prevent diabetes-or galactosaemia-associated structural changes in the retinal vasculature and the RPE (Frank et al, 1983;Robison et al, 1983Robison et al, , 1989) and breakdown of the BRB in diabetic and galactosaemic rats (Cunha-Vaz et al, 1985;Lightman et al, 1987;Williamson et al, 1987;Vinores et al, 1990b, c). AR has been demonstrated by light microscopy in diabetic human retina and RPE, and its expression correlates with the severity and duration of the disease (Vinores et al, 1988), but AR has not previously been demonstrated in RVE cells, which are the primary cells to lose their barrier function in diabetic retinopathy.…”

Biochemical Markers of Diabetic Microangiopathy

“…Examples may be an increased sorbitol/polyol pathway activity leading to intracellular osmotic changes or to decreased pools of myoinositol [3]. Such changes may be prevented by aldose reductase inhibitors [4]. So far no convincing clinical effects of such agents have been demonstrated in humans, especially when effects are weighed against side-effects.…”

Reactive Oxygen Species and Acute Modulation of Albumin Microvascular Leakage in the Microcirculation of Diabetic Rats in vivo

“…It has also been demonstrated to be implicated in decreased endothelium-dependent dilating capacity associated with hyperglycemia or diabetes [9]. Another aspect in which oxidative mechanisms could potentially be involved is the generalized increase in transvascular passage of macromolecules [10]described in different types of diabetes in animals [11]and also found in patients [12, 13]even at very early stages of the disease [14]. Indeed, several mechanisms have been proposed to explain this increase in transvascular passage of macromolecules associated with diabetes.…”