Evaluation of alpha(1)-adrenoceptor antagonist on diabetes-induced changes in peripheral nerve function, metabolism, and antioxidative defense.
The role for nerve blood flow (NBF) vs. other factors in motor nerve conduction (MNC) slowing in short-term diabetes was assessed by evaluating alpha(1)-adrenoceptor antagonist prazosin on NBF, MNC, as well as metabolic imbalances and oxidative stress in the neural tissue. Control and diabetic rats were treated with or without prazosin (5 mg.kg(-1).d(-1) for 3 wk). NBF was measured by hydrogen clearance. Both endoneurial vascular conductance and MNC velocity were decreased in diabetic rats vs. controls, and this decrease was prevented by prazosin. Free NAD(+):NADH ratios in mitochondrial cristae, matrix, and cytosol assessed by metabolite indicator method, as well as phosphocreatine levels and phosphocreatine/creatine ratios, were decreased in diabetic rats, and this reduction was ameliorated by prazosin. Neither diabetes-induced accumulation of two major glycation agents, glucose and fructose, as well as sorbitol and total malondialdehyde plus 4-hydroxyalkenals nor depletion of myo-inositol, GSH, and taurine or decrease in (Na/K)-ATP-ase activity were affected by prazosin. In conclusion, decreased NBF, but not metabolic imbalances or oxidative stress in the neural tissue, is a key mechanism of MNC slowing in short-term diabetes. Further experiments are needed to estimate whether preservation of NBF is sufficient for prevention of nerve dysfunction and morphological abnormalities in long-standing diabetes or whether the aforementioned metabolic imbalances closely associated with impaired neurotropism are of greater importance in advanced than in early diabetic neuropathy.
Obrosova
I G
IG
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0354, USA. iobrosso@umich.edu
Van Huysen
C
C
Fathallah
L
L
Cao
X
X
Stevens
M J
MJ
Greene
D A
DA
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003401:Creatine / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D005978:Glutathione / Q000032:analysis; D006601:Hexoses / Q000032:analysis; D007294:Inositol / Q000032:analysis; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D012584:Sciatic Nerve / Q000098:blood supply / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013012:Sorbitol / Q000032:analysis; D013654:Taurine / Q000032:analysis
D000317:Adrenergic alpha-Antagonists; D000975:Antioxidants; D001786:Blood Glucose; D006601:Hexoses; D018340:Receptors, Adrenergic, alpha-1; D009243:NAD; D013654:Taurine; D007294:Inositol; D008315:Malondialdehyde; D013012:Sorbitol; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione; D003401:Creatine; D011224:Prazosin