Neurovascular interactions between aldose reductase and angiotensin-converting enzyme inhibition in diabetic rats.
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-tolyl)acetanilide), 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 (ED(50) approximately 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 approximately 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.
Cotter
M A
MA
Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill Aberdeen, AB25 2ZD, Scotland, UK.
Mirrlees
D J
DJ
Cameron
N E
NE
D000083:Acetanilides / Q000494:pharmacology* / Q000627:therapeutic use; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000201:enzymology* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D017706:Lisinopril / Q000494:pharmacology* / Q000627:therapeutic use; D009431:Neural Conduction / Q000187:drug effects; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D012584:Sciatic Nerve / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D014664:Vasodilation / Q000187:drug effects
D000083:Acetanilides; D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D013450:Sulfones; C090184:ZENECA ZD 5522; D017706:Lisinopril; D000449:Aldehyde Reductase