Pharmacological manipulation of vascular endothelium function in non-diabetic and streptozotocin-diabetic rats: effects on nerve conduction, hypoxic resistance and endoneurial capillarization.
We examined the potential for some of the abnormalities of vascular endothelium found in diabetes mellitus to cause neuropathic changes. Non-diabetic rats were treated for 2 months with the cyclo-oxygenase inhibitor flurbiprofen (5 mg.kg-1.day-1) to reduce prostacyclin production, the nitric oxide synthase inhibitor NG-nitro-L-arginine (5 or 25 mg.kg-1.day-1), or combined treatment. There were dose-dependent reductions in sciatic motor and saphenous sensory conduction velocity. The two inhibitors acted synergistically, thus, the 5-6% motor conduction deficits (p < 0.01) produced by either flurbiprofen or NG-nitro-L-arginine (5 mg.kg-1.day-1) increased to 17% (p < 0.001) for combined treatment. With NG-nitro-L-arginine (25 mg.kg-1.day-1) and flurbiprofen, motor and sensory conduction velocity were reduced by 23% (p < 0.001) and 12% (p < 0.001), respectively, matching the deficits following 2-month streptozotocin diabetes. NG-nitro-L-arginine (25 mg.kg-1.day-1) and flurbiprofen together produced a 13% prolongation of the time taken for 80% hypoxic conduction failure in vitro (p < 0.05) and a 10% reduction in sciatic capillary density. A second investigation tested an alternative hypothesis that overproduction of nitric oxide was responsible for vascular-related complications in diabetes, the prediction being that NG-nitro-L-arginine (5 mg.kg-1.day-1) would prevent nerve dysfunction. However, rather than prophylaxis during 2-month streptozotocin diabetes, treatment exacerbated nerve abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)
Cameron
N E
NE
Department of Biomedical Sciences, University of Aberdeen, Scotland, UK.
Cotter
M A
MA
Dines
K C
KC
Maxfield
E K
EK
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002196:Capillaries / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D015687:Cell Hypoxia; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D005480:Flurbiprofen / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009431:Neural Conduction / Q000187:drug effects*; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D019335:Nitroarginine; D010525:Peripheral Nerves / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D012584:Sciatic Nerve / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology*
D019335:Nitroarginine; D005480:Flurbiprofen; D001120:Arginine