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

Mary Anne Cotter, D. J. Mirrlees, Norman E Cameron

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Increased polyol pathway flux has been linked to nerve complications in diabetic 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 vasoconstriction. The aim was to assess whether promotion of vasodilation by treatment with the aldose reductase inhibitor, ZD5522 (3 ' ,5 ' -dimethyl-4 ' -nitromethylsulphonyl-2-(2-toyl)acretanilide coupled with reduced vasoconstriction using the angiotensin-converting enzyme inhibitor, lisinopril, interacted positively to improve neurovascular function. After 8 weeks of streptozotocin-induced diabetes, sciatic nerve blood flow and motor conduction velocity were 51% and 21% reduced, respectively. Two weeks of Lisinopril treatment 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 perfusion. However, when combined, blood flow and conduction velocity reached the nondiabetic 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 enzyme and aldose reductase inhibition in diabetic rats. This points to a potential therapeutic benefit, which requires evaluation in clinical trials. (C) 2001 Elsevier Science B.V. All rights reserved.

Original languageEnglish
Pages (from-to)223-230
Number of pages7
JournalEuropean Journal of Pharmacology
Volume417
Issue number3
DOIs
Publication statusPublished - 2001

Keywords

  • neuropathy
  • diabetic
  • rat
  • aldose reductase
  • angiotensin-converting enzyme
  • nerve conduction
  • blood flow
  • ENDONEURIAL BLOOD-FLOW
  • ALPHA-LIPOIC ACID
  • NITRIC-OXIDE
  • CORPUS CAVERNOSUM
  • NERVE-CONDUCTION
  • POLYOL PATHWAY
  • SORBITOL DEHYDROGENASE
  • OXYGEN-TENSION
  • AORTIC RINGS
  • VITAMIN-E

Cite this

Neurovascular interactions between aldose reductase and angiotensin-converting enzyme inhibition in diabetic rats. / Cotter, Mary Anne; Mirrlees, D. J.; Cameron, Norman E.

In: European Journal of Pharmacology, Vol. 417, No. 3, 2001, p. 223-230.

Research output: Contribution to journalArticle

Cotter, Mary Anne ; Mirrlees, D. J. ; Cameron, Norman E. / Neurovascular interactions between aldose reductase and angiotensin-converting enzyme inhibition in diabetic rats. In: European Journal of Pharmacology. 2001 ; Vol. 417, No. 3. pp. 223-230.
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AU - Mirrlees, D. J.

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N2 - Increased polyol pathway flux has been linked to nerve complications in diabetic 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 vasoconstriction. The aim was to assess whether promotion of vasodilation by treatment with the aldose reductase inhibitor, ZD5522 (3 ' ,5 ' -dimethyl-4 ' -nitromethylsulphonyl-2-(2-toyl)acretanilide coupled with reduced vasoconstriction using the angiotensin-converting enzyme inhibitor, lisinopril, interacted positively to improve neurovascular function. After 8 weeks of streptozotocin-induced diabetes, sciatic nerve blood flow and motor conduction velocity were 51% and 21% reduced, respectively. Two weeks of Lisinopril treatment 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 perfusion. However, when combined, blood flow and conduction velocity reached the nondiabetic 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 enzyme and aldose reductase inhibition in diabetic rats. This points to a potential therapeutic benefit, which requires evaluation in clinical trials. (C) 2001 Elsevier Science B.V. All rights reserved.

AB - Increased polyol pathway flux has been linked to nerve complications in diabetic 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 vasoconstriction. The aim was to assess whether promotion of vasodilation by treatment with the aldose reductase inhibitor, ZD5522 (3 ' ,5 ' -dimethyl-4 ' -nitromethylsulphonyl-2-(2-toyl)acretanilide coupled with reduced vasoconstriction using the angiotensin-converting enzyme inhibitor, lisinopril, interacted positively to improve neurovascular function. After 8 weeks of streptozotocin-induced diabetes, sciatic nerve blood flow and motor conduction velocity were 51% and 21% reduced, respectively. Two weeks of Lisinopril treatment 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 perfusion. However, when combined, blood flow and conduction velocity reached the nondiabetic 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 enzyme and aldose reductase inhibition in diabetic rats. This points to a potential therapeutic benefit, which requires evaluation in clinical trials. (C) 2001 Elsevier Science B.V. All rights reserved.

KW - neuropathy

KW - diabetic

KW - rat

KW - aldose reductase

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KW - nerve conduction

KW - blood flow

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KW - ALPHA-LIPOIC ACID

KW - NITRIC-OXIDE

KW - CORPUS CAVERNOSUM

KW - NERVE-CONDUCTION

KW - POLYOL PATHWAY

KW - SORBITOL DEHYDROGENASE

KW - OXYGEN-TENSION

KW - AORTIC RINGS

KW - VITAMIN-E

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DO - 10.1016/S0014-2999(01)00909-8

M3 - Article

VL - 417

SP - 223

EP - 230

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 3

ER -