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 vasodilator agents have been studied in 14-day streptozotocin-diabetic rats. The effects of treatment with the aldose reductase inhibitor, ponalrestat, on these responses have also been investigated. 2. Maximum contractile responses and aortic sensitivity to phenylephrine were significantly enhanced in 14-day diabetic aortae. 3. In contrast, endothelium-dependent relaxations to carbachol were depressed in diabetic rats, whilst endothelium-independent relaxations to forskolin and sodium nitroprusside were unchanged. 4. Pretreatment with ponalrestat (25 mg kg-1, daily) prevented both the enhanced maximum contractile responses to phenylephrine and the depressed endothelium-dependent relaxations to carbachol in aortae from 14-day diabetic rats. Ponalrestat however, had no effect on the reduced phenylephrine EC50 values observed in tissues from diabetic animals. 5. It is concluded that ponalrestat prevents the depression of endothelium-dependent aortic relaxations induced by diabetes of 14 days duration, suggesting that the polyol pathway is involved in these vascular changes. Ponalrestat does not prevent the increase in aortic sensitivity to alpha 1-adrenoceptor agonists.
Otter
D J
DJ
Department of Biomedical Science, University of Sheffield.
Chess-Williams
R
R
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology*; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010793:Phthalazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects
D010793:Phthalazines; D018340:Receptors, Adrenergic, alpha-1; D009599:Nitroprusside; D005576:Colforsin; D010656:Phenylephrine; C042829:ponalrestat; D002217:Carbachol; D000449:Aldehyde Reductase