Reversal of defective peripheral nerve conduction velocity, nutritive endoneurial blood flow, and oxygenation by a novel aldose reductase inhibitor, WAY-121,509, in streptozotocin-induced diabetic rats.
The main aim was to investigate whether 1 month of aldose reductase inhibitor treatment could correct a deficit in sciatic nerve nutritive blood flow following 1 month of untreated streptozotocin-induced diabetes in rats. Treatment was with two doses of WAY-121,509, both of which completely blocked neuronal sorbitol accumulation. The high dose fully corrected a motor conduction velocity deficit, whereas the low dose caused 51.3% amelioration. Nutritive endoneurial blood flow, monitored by hydrogen clearance, was 43.4% reduced after 1 month of diabetes. This was completely corrected by the high dose of WAY-121,509. In addition, vascular conductance was supranormal and there was a decrease in arteriovenous shunt flow. Low dose treatment caused a 55.6% improvement of the nutritive endoneurial blood flow deficit, paralleling the conduction velocity effect. WAY-121,509 did not alter nerve perfusion in nondiabetic rats. Data from multiple sciatic nerve penetrations by oxygen sensitive microelectrodes revealed a 42.0% deficit in mean endoneurial oxygen tension with diabetes, whereas tensions were in the nondiabetic range for high dose WAY-121,509 treatment. Thus, the data highlight neurovascular actions of aldose reductase inhibition, and suggest that neuronal polyol pathway metabolite levels are a poor predictor of functional efficacy.
Cameron
N E
NE
Department of Biomedical Sciences, University of Aberdeen, Marischal College, Scotland.
Cotter
M A
MA
Dines
K C
KC
Hohman
T C
TC
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005632:Fructose / Q000378:metabolism; D007294:Inositol / Q000378:metabolism; D008297:Male; D009431:Neural Conduction / Q000187:drug effects*; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow; D012584:Sciatic Nerve / Q000098:blood supply / Q000187:drug effects*; D013012:Sorbitol / Q000378:metabolism
D001786:Blood Glucose; D004791:Enzyme Inhibitors; C091470:WAY 121-509; D005632:Fructose; D007294:Inositol; D013012:Sorbitol; D000449:Aldehyde Reductase; D010100:Oxygen