Prevention of basement membrane thickening in retinal capillaries by a novel inhibitor of aldose reductase, tolrestat.
A diabetic-like thickening of retinal capillary basement membranes induced in rats fed for 207 consecutive days a diet containing 50% galactose was prevented by the addition to the diet of tolrestat, a potent, structurally novel inhibitor of aldose reductase. Analysis of electron micrographs (X 25,000) of capillaries from the outer plexiform layer of the retina by computer planimetry showed that the basement membranes were approximately twofold thicker in rats fed galactose than in those fed either a standard diet or a diet containing galactose and tolrestat in doses of 43 or 57 mg/kg/day. The thickening of basement membranes in galactose-fed rats was accompanied by other ultrastructural alterations mimicking changes typical of diabetic microangiopathy, such as multilamination and the formation of vacuoles and dense inclusions. Therefore, the galactosemic rat represents a useful model for studying basement membrane-related complications of diabetes and their possible prevention by aldose reductase inhibitors.
Robison
W G
WG
Kador
P F
PF
Akagi
Y
Y
Kinoshita
J H
JH
Gonzalez
R
R
Dvornik
D
D
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001485:Basement Membrane / Q000187:drug effects* / Q000648:ultrastructure; D002196:Capillaries / Q000187:drug effects / Q000648:ultrastructure; D002386:Cataract / Q000201:enzymology / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000201:enzymology / Q000378:metabolism; D005690:Galactose / Q000494:pharmacology; D008297:Male; D008854:Microscopy, Electron; D009281:Naphthalenes / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012171:Retinal Vessels / Q000187:drug effects* / Q000648:ultrastructure; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
D009281:Naphthalenes; C040550:tolrestat; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase; D005690:Galactose