Prevention of Hemodynamic and Vascular Albumin Filtration Changes in Diabetic Rats by Aldose Reductase Inhibitors

Abstract

This study investigated hemodynamic changes in diabetic rats and their relationship to changes in vascular albumin permeation and increased metabolism of glucose to sorbitol. The effects of 6 wk of streptozocin-induced diabetes and three structurally different inhibitors of aldose reductase were examined on 1) regional blood flow (assessed with 15-microns 85Sr-labeled microspheres) and vascular permeation by 125I-labeled bovine serum albumin (BSA) and 2) glomerular filtration rate (assessed by plasma clearance of 57Co-labeled EDTA) and urinary albumin excretion (determined by radial immunodiffusion assay). In diabetic rats, blood flow was significantly increased in ocular tissues (anterior uvea, posterior uvea, retina, and optic nerve), sciatic nerve, kidney, new granulation tissue, cecum, and brain. 125I-BSA permeation was increased in all of these tissues except brain. Glomerular filtration rate and 24-h urinary albumin excretion were increased 2- and 29-fold, respectively, in diabetic rats. All three aldose reductase inhibitors completely prevented or markedly reduced these hemodynamic and vascular filtration changes and increases in tissue sorbitol levels in the anterior uvea, posterior uvea, retina, sciatic nerve, and granulation tissue. These observations indicate that early diabetes-induced hemodynamic changes and increased vascular albumin permeation and urinary albumin excretion are aldose reductase-linked phenomena. Discordant effects of aldose reductase inhibitors on blood flow and vascular albumin permeation in some tissues suggest that increased vascular albumin permeation is not entirely attributable to hemodynamic changes. We hypothesize that 1) increases in blood flow may reflect impaired contractile function of smooth muscle cells in resistance arterioles and 2) increases in vascular 125I-BSA permeation and urinary albumin excretion reflect impaired vascular barrier functional integrity in addition to increased hydraulic conductance secondary to microvascular hypertension associated with decreased vascular resistance.

Angiotensin AT 1 receptor antagonism normalizes retinal blood flow and acetylcholine-induced vasodiliation in normotensive diabetic rats

“…While our group and others have reported that there is a decrease in RBF in diabetic animal models and in patients with Type 1 diabetes [8,9,10,11], other groups have reported that diabetes increases RBF [44,45,46]. The different results from these groups could be related to the methodologies used (video fluorescein angiography and laser Doppler velocimetry), the duration of diabetes, whether or not clinically observable diabetic retinopathy was present, the blood glucose levels at the time of the measurement, and the level of glycaemic control or haemoglobin A 1c in the studied patients [20,47].…”

Sorbinil does not prevent hyperfiltration, elevated ultrafiltration pressure and albuminuria in streptozotocin-diabetic rats

“…Since then numerous experimental studies have been carried out to test this hypothesis. These experimental studies of activation of the polyol metabolic pathway and its role in the diabetes-associated renal alterations have so far not given any conclusive results [16][17][18][19][20][21][22]. Some of the inconsistencies in results might be attributed to differences in the severity of diabetes.…”

“…In studies where an effect of aldose reductase inhibitors (ARI) on renal haemodynamics was noticed, typical renal effects of diabetes, e.g. kidney enlargement and/or hyperfiltration were generally absent or not very prominent indicating that the state of diabetes was very mild [16][17][18]. In addition, the causal relationship between increased polyol metabolism and the level of hyperperfusion was difficult to evaluate in these studies since data on renal tissue sorbitol content were not available.…”

Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?

“…One such mechanism is linked to increased flux through the polyol or hexosamine pathways which is associated with subsequent alterations in the redox state of pyridine nucleotides. 37 Accumulation of sorbitol in retinal cells is dependant on the activity of aldose reductase and this may impinge on a range of pathways and contribute to diabetic retinopathy. 38 Also de novo synthesis of diacylglycerol (DAG) leading to the over-activation of several isoforms of protein kinase C (PKC), 39 excessive production of free radicals leading to oxidative stress, 40,41 changes in blood rheology and haemodynamics, 42,43 and over-activation of the renin-angiotensin system 44 contribute significantly to retinopathy as diabetes progresses.…”