Effect of aldose reductase inhibitor ONO 2235 on reduced sympathetic nervous system activity and peripheral nerve disorders in STZ-induced diabetic rats.
To test the hypothesis that inhibitors of aldose reductase, a key enzyme for polyol synthesis, prevent the decrease of sympathetic nervous system (SNS) activity and improve motor nerve conduction velocity (MNCV) through the reduction of sorbitol accumulation in streptozocin (STZ)-induced diabetic rats, norepinephrine (NE) turnover (reliable indicator of SNS activity in the interscapular brown adipose tissue (IBAT), heart, and pancreas), and MNCV were measured in untreated STZ-induced diabetic rats, STZ-induced diabetic rats treated with an aldose reductase inhibitor (ARI) (ONO 2235, 50 mg X kg-1 X day-1, orally), STZ-induced diabetic rats treated with insulin therapy, control rats, and control rats treated with ARI. As expected, results from studies with the inhibition of NE biosynthesis with alpha-methyl-p-tyrosine or radiolabeled NE to measure NE turnover demonstrated significant reductions in SNS activity in IBAT, heart, and pancreas of untreated STZ-induced diabetic rats, compared with those in control rats. MNCV determined with the tail nerve was significantly reduced in untreated STZ-induced diabetic rats, compared with that of the controls. Both daily ARI treatment and insulin therapy in STZ-induced diabetic rats prevented partially but significantly the decrease of NE turnover in IBAT, heart, and pancreas, ameliorated MNCV, and reduced sorbitol accumulation in the nerve tissue and red blood cells. ARI treatment in control rats had no effect on NE turnover, MNCV, or sorbitol content. These results suggest that STZ-induced diabetic rats had not only motor neuropathy but also sympathetic nervous dysfunction and that ARI treatment might prevent these as well as insulin therapy does through the reduction of sorbitol accumulation.
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000188:drug therapy*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D004912:Erythrocytes / Q000032:analysis; D005260:Female; D008781:Methyltyrosines; D009431:Neural Conduction / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy*; D051381:Rats; D011919:Rats, Inbred Strains; D012236:Rhodanine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D012584:Sciatic Nerve / Q000032:analysis; D013012:Sorbitol / Q000032:analysis; D013311:Streptozocin / Q000494:pharmacology; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*; D013564:Sympathetic Nervous System / Q000187:drug effects*; D013844:Thiazoles / Q000627:therapeutic use*; D053778:Thiazolidines; D014284:Triiodothyronine / Q000097:blood; D019805:alpha-Methyltyrosine
D008781:Methyltyrosines; D013844:Thiazoles; D053778:Thiazolidines; D014284:Triiodothyronine; C038131:epalrestat; D013012:Sorbitol; D013311:Streptozocin; D019805:alpha-Methyltyrosine; D012236:Rhodanine; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase; D009638:Norepinephrine