Reduced nerve blood flow in diabetic rats: relationship to nitric oxide production and inhibition of aldose reductase.
This study examined links between impaired nitric oxide production in the sciatic endoneurium, nerve blood flow, and polyol pathway flux, to test the hypothesis that reduced nerve blood flow might be compromised by competition for NADPH between aldose reductase and nitric oxide synthase. Sciatic nerves of streptozotocin-diabetic rats showed reduced laser Doppler flux (by 51% or 63%; both p<0.05)-indicative of reduced nerve blood flow-and reduced motor nerve conduction velocity (17% in two experiments; p<0.05). Acute interruption of nitric oxide production in the sciatic nerves of control rats, via endoneurial injection of N omega-nitro-D-arginine methyl ester (L-NAME), caused a local reduction (of 64%; p<0.001) in nerve Doppler flux. This was reversed by either L-arginine or sodium nitroprusside. The response to L-NAME was greatly reduced in diabetic rats (only 22% reduction; p<0.01), though both L-arginine and SNP caused marked increases in flux. Chronic inhibition of aldose reductase in diabetic rats (with either sorbinil or imirestat at a range of doses) had little effect on resting sciatic nerve Doppler flux, though both inhibitors normalized conduction velocity. Both aldose reductase inhibitors reduced sorbitol pathway intermediates in a dose-related manner. These findings do not support the proposition that aldose reductase inhibitors normalise conduction velocity by mechanisms dependent upon either normalization of endoneurial nitric oxide or nerve blood flow. Instead, a mechanism based upon more direct effects on axon or Schwann cell function is favoured.
Tomlinson
D R
DR
Department of Pharmacology, School of Medical Sciences, Queen Mary and Westfield College, London, UK.
Dewhurst
M
M
Stevens
E J
EJ
Omawari
N
N
Carrington
A L
AL
Vo
P A
PA
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017078:Laser-Doppler Flowmetry; D008297:Male; D009046:Motor Neurons / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009431:Neural Conduction / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000098:blood supply*
D004791:Enzyme Inhibitors; D009599:Nitroprusside; D009569:Nitric Oxide; D001120:Arginine; D000449:Aldehyde Reductase; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester