Present experiments were designed to investigate whether the facilitated
polyol pathway is involved in the augmentation of intimal
hyperplasia with
hyperglycemia. Twelve weeks after a single bolus
intravenous injection of
alloxan (100 mg/kg) or saline, rabbits underwent a unilateral endothelial denudation of the carotid artery. Intimal
hyperplasia was evident 4 weeks after denudation and significantly augmented in hyperglycemic animals treated with
alloxan. This effect was accompanied by the enhanced accumulation of endogenous NOS inhibitors (N(G)-monomethyl-
l-arginine [
l-NMMA] and asymmetric,
N(G),N(G)-dimethyl-l-arginine [ADMA]) in regenerated endothelial cells, impairment of NO production and release, and enhanced accumulation of
endothelin-1 (ET-1) within the vessel wall.
Sorbitol levels in aortic endothelial cells and within the smooth muscle layer were significantly increased with
hyperglycemia. All these changes associated with
hyperglycemia were significantly reduced in animals treated with the selective
aldose reductase inhibitor
fidarestat (3 mg/kg/d). These findings suggest that the facilitated
polyol pathway possibly plays an important role for the augmentation of intimal
hyperplasia caused by the hyperglycemic state.