THE EFFECTS OF ALDOSE REDUCTASE INHIBITION WITH PONALRESTAT ON CHANGES IN VASCULAR FUNCTION IN STREPTOZOTOCIN-DIABETIC RATS

1 The responses of rat isolated aortae to vasoconstrictor and vasodila tor agents have been studied in 14-day streptozotocin-diabetic rats. T he effects of treatment with the aldose reductase inhibitor, ponalrest at, on these responses have also been investigated. 2 Maximum contract ile responses and aortic sensitivity to phenylephrine were significant ly enhanced in 14-day diabetic aortae. 3 In contrast, endothelium-depe ndent relaxations to carbachol were depressed in diabetic rats, whilst endothelium-independent relaxations to forskolin and sodium nitroprus side were unchanged. 4 Pretreatment with ponalrestat (25 mg kg(-1), da ily) prevented both the enhanced maximum contractile responses to phen ylephrine and the depressed endothelium-dependent relaxations to carba chol in aortae from 14-day diabetic rats. Ponalrestat however, had no effect on the reduced phenylephrine EC(50) values observed in tissues from diabetic animals. 5 It is concluded that ponalrestat prevents the depression of endothelium-dependent aortic relaxations induced by dia betes of 14 days duration, suggesting that the polyol pathway is invol ved in these vascular changes. Ponalrestat does not prevent the increa se in aortic sensitivity to alpha(1)-adrenoceptor agonists.