Rapid reversal by aminoguanidine of the neurovascular effects of diabetes in rats: modulation by nitric oxide synthase inhibition.
Aminoguanidine treatment prevents the development of nerve conduction velocity (NCV) deficits and some renal and retinal complications in diabetic rats. Pharmacological actions include inhibition of the formation of advanced glycosylation end products (AGEs) and nitric oxide (NO) synthase. The aims of the study were to determine the extent to which diabetic NCV and nerve blood flow deficits could be corrected by aminoguanidine in an intervention study, to assess the time course of drug action, and to examine the effects of cotreatment with the NO synthase inhibitor, NG-nitro-L-arginine (NOLA). A 19.3% +/- 0.9% reduction in sciatic motor NCV after 4 weeks of untreated diabetes was corrected 86.6% +/- 3.7% by aminoguanidine treatment for a further 4 weeks. Time-course studies showed that 50% of the maximal effect was attained within 6 days. Sciatic endoneurial capillary blood flow, reduced approximately 45% by diabetes, was corrected 85.6% +/- 12.1% by aminoguanidine treatment. The NCV and blood flow effects of aminoguanidine were completely blocked by cotreatment with NOLA. Thus, the data support a neurovascular mechanism for aminoguanidine involving improved NO action. The rapidity of aminoguanide's effect is consistent with inhibition of free radical production by autoxidative glycosylation or glycoxidation.
Cameron
N E
NE
Department of Biomedical Sciences, University of Aberdeen, Scotland, UK.
Cotter
M A
MA
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000627:therapeutic use; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D017127:Glycation End Products, Advanced; D006146:Guanidines / Q000627:therapeutic use*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D001120:Arginine; D019001:Nitric Oxide Synthase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester