Neurovascular interactions between aldose reductase and angiotensin-converting enzyme inhibition in diabetic rats

Increased polyol pathway flux has been linked to nerve complications in dia betic rats, which are attenuated by aldose reductase inhibitors, defective nitric oxide-mediated vasodilation being a particular target. Diabetes also elevates the endothelial angiotensin system, increasing vasa nervorum vaso constriction. The aim was to assess whether promotion of vasodilation by tr eatment with the aldose reductase inhibitor, ZD5522 (3 ' ,5 ' -dimethyl-4 ' -nitromethylsulphonyl-2-(2-toyl)acretanilide coupled with reduced vasocons triction using the angiotensin-converting enzyme inhibitor, lisinopril, int eracted positively to improve neurovascular function. After 8 weeks of stre ptozotocin-induced diabetes, sciatic nerve blood flow and motor conduction velocity were 51% and 21% reduced, respectively. Two weeks of Lisinopril tr eatment dose-dependently corrected the conduction deficit (ED50 similar to 0.9 mg kg(-1)). Low-dose Lisinopril (0.3 mg kg(-1)) or ZD5522 (0.25 mg kg(- 1)) had modest corrective (10-20%) effects on nerve conduction and perfusio n. However, when combined, blood flow and conduction velocity reached the n ondiabetic range. The ZD5522 dose used gave a similar to 45% nerve sorbitol reduction but had no significant effect on fructose content; lisinopril co -treatment did not alter ZD5522 action on polyols. Thus, there was a marked neurovascular synergistic interaction between angiotensin-converting enzym e and aldose reductase inhibition in diabetic rats. This points to a potent ial therapeutic benefit, which requires evaluation in clinical trials. (C) 2001 Elsevier Science B.V. All rights reserved.