Aldose reductase inhibition, nerve perfusion, oxygenation and function in streptozotocin-diabetic rats: dose-response considerations and independence from a myo-inositol mechanism

Diabetologia. 1994 Jul;37(7):651-63. doi: 10.1007/BF00417688.


We examined the effects of aldose reductase inhibition on nerve biochemistry and function, blood flow and endoneurial oxygenation in experimental diabetes mellitus. After 1 month untreated diabetes in rats, treatment with the novel sulphonylnitromethane aldose reductase inhibitor, ZENECA ZD5522, prevented a progressive increase in sciatic nerve resistance to hypoxic conduction failure (p < 0.05). Motor conduction velocity deficits after 4 months untreated diabetes were rapidly returned to normal within 12 days (p < 0.0001) by ZD5522 treatment. Following 2-months untreated diabetes, examination of 1 month ZD5522 treatment dose-response relationships for correction of nerve sorbitol and fructose accumulations and reduction in myo-inositol concentration, sciatic motor and saphenous sensory conduction velocity and sciatic blood flow by laser-Doppler flowmetry revealed poor agreement between nerve function and biochemical indices. In addition, polyol accumulation differed between sciatic and saphenous nerves, the latter showing ten-fold lower sorbitol concentrations. Laser-Doppler blood flow was 60% decreased by untreated diabetes (p < 0.001) and there was a strong correlation between ZD5522-mediated increases in blood flow and conduction velocity (p < 0.0001). Measurement of nutritive endoneurial blood flow by microelectrode polarography and hydrogen clearance showed 44% and 45% deficits for 1 and 2 months untreated diabetes (p < 0.001) that were prevented by ponalrestat and ZD5522 treatments, respectively. In contrast, 2 months myo-inositol treatment from diabetes induction did not prevent reduction in blood flow or sciatic motor conduction velocity. A 37% reduction in endoneurial oxygen tension after 2 months diabetes (p < 0.001) was completely prevented by ZD5522 treatment (p < 0.001). The data show that a very high degree of polyol pathway blockade is necessary to correct nerve functional deficits and that aldose reductase inhibitors have a neurovascular action that does not depend on restoration of nerve myo-inositol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / pharmacology*
  • Aldehyde Reductase / antagonists & inhibitors*
  • Animals
  • Blood Flow Velocity / drug effects
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Experimental / physiopathology*
  • Dose-Response Relationship, Drug
  • Inositol / metabolism
  • Male
  • Motor Neurons / drug effects
  • Motor Neurons / physiology
  • Neural Conduction / drug effects
  • Neural Conduction / physiology
  • Oxygen / metabolism*
  • Perfusion
  • Peripheral Nerves / blood supply
  • Peripheral Nerves / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Sciatic Nerve / blood supply
  • Sciatic Nerve / physiology*
  • Sulfones / pharmacology*


  • Acetanilides
  • Blood Glucose
  • Sulfones
  • ZENECA ZD 5522
  • Inositol
  • Aldehyde Reductase
  • Oxygen