Polyol pathway inhibition improves age‐related vascular dysfunction in rats

Abstract

Altered glucose metabolism may contribute to age-related vascular dysfunction. Aging alters expression of polyol pathway enzymes and hence substrate flux via these enzymes. Aldose reductase (AR) is the rate-limiting enzyme in the polyol pathway. The effect of AR inhibitor Zopolrestat (ARI) on improving vascular dysfunction in aged rats was examined. Endothelium dependent relaxation (EDR) was measured in aortic rings from young and aged (4 vs. 26 months) Fisher 344 rats in organ baths. EDR to acetylcholine (Ach; 10−8–10−4M) was measured as % relaxation to phenylephrine±SEM. Rings were exposed to ARI (10 mM), and EDR with ARI and after washout were measured. EDR was impaired in aged rats compared with young rats. Exposure of the aged rings to ARI alone resulted in a significant vasodilation (73 ± 5). Further addition of Ach to these rings produced EDR similar to that seen in young rats. Following washout EDR was impaired, indicating that protection by ARI is reversible. The nitric oxide (NO) synthase inhibitor L-NAME (100 μM) did not prevent vasodilation to ARI, suggesting that improvement of EDR by ARI is not mediated by an increase in NO synthase-derived NO production. These data indicate that polyol pathway inhibitors may ameliorate agerelated vascular dysfunction. Supported by NIH HL61783