Action of Aldose Reductase Inhibitors

Most aldose reductase inhibitors (e.g. sorbinil, alrestatin, tolrestat and ponalrestat) inhibit the enzyme in a non-competitive or uncompetitive way - they compete neither with the substrate nor with the cofactor (NADPH). Therefore, an inhibitory binding site in the enzyme is postulated (Sarges, 1989). 

Aldose reductase is present in the Schwann cell body but not in the axon. Activation of the polyol pathway depletes myo-inositol and inactivates Na/K-ATPase activity of nerve cells, leading to a reduction in the nerve conduction velocity, at least in diabetic animals, myo-inositol is important for the phosphoinositide-mediated regulation of 

Loss of mural cells (pericytes) in the retinal microcapillaries is a typical event in diabetic retinopathy. These mural cells contain aldose reductase and accumulate sorbitol in experimental hyperglycaemia (Buzney et al., 1977), leading to degenerative changes implying participation of the polyol pathway in cell death. 

Use of aldose reductase inhibitors prevents the loss of pericytes in animals maintained on high-galactose diets (Robinson et al., 1989). Also, in streptozocin-diabetic or fructose-fed rats the development of retinopathic changes was prevented by aldose reductase inhibitors (Kojima et al., 1985). In contrast, collagen synthesis by retinal pericytes was unaffected (Li et al., 1985). 

The overall accumulation of sorbitol in the retina of diabetic rats seems to be of little significance, but the distribution of the polyols in the different cellular locations could produce osmotic force. In alloxan-diabetic animals the above-mentioned triad of myo-inositol depletion, reduced Na/K-ATPase activity and activation of PKC following accumulation of sorbitol is seen and can be prevented by inhibition of aldose reductase (MacGregor and Matschinsky, 1985), although the impact of this system on the generation of diabetic retinopathy remains to be established. 

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