Prevention of hemodynamic and vascular albumin filtration changes in diabetic rats by aldose reductase inhibitors.
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.
Tilton
R G
RG
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110.
Chang
K
K
Pugliese
G
G
Eades
D M
DM
Province
M A
MA
Sherman
W R
WR
Kilo
C
C
Williamson
J R
JR
D000419:Albuminuria; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005449:Fluorenes / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects*; D006827:Hydantoins / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D007457:Iodine Radioisotopes; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects*; D012710:Serum Albumin, Bovine; D013012:Sorbitol / Q000378:metabolism; D013324:Strontium; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*; D014655:Vascular Resistance / Q000187:drug effects
D005449:Fluorenes; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D007457:Iodine Radioisotopes; D009281:Naphthalenes; C052241:imirestat; C040550:tolrestat; D012710:Serum Albumin, Bovine; D013012:Sorbitol; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase; C026411:sorbinil; D013324:Strontium