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Protein kinase C effects on nerve function, perfusion, Na(+), K(+)-ATPase activity and glutathione content in diabetic rats.
- Source :
-
Diabetologia [Diabetologia] 1999 Sep; Vol. 42 (9), pp. 1120-30. - Publication Year :
- 1999
-
Abstract
- Aims/hypothesis: Increased protein kinase C activity has been linked to diabetic vascular complications in the retina and kidney, which were attenuated by protein kinase C antagonist treatment. Neuropathy has a vascular component, therefore, the aim was to assess whether treatment with WAY151 003 or chelerythrine, inhibitors of protein kinase C regulatory and catalytic domains respectively, could correct nerve blood flow, conduction velocity, Na(+),K(+)-ATPase, and glutathione deficits in diabetic rats.<br />Methods: Diabetes was induced by streptozotocin. Sciatic nerve conduction velocity was measured in vivo and sciatic endoneurial perfusion was monitored by microelectrode polarography and hydrogen clearance. Glutathione content and Na(+),K(+)-ATPase activity were measured in extracts from homogenised sciatic nerves.<br />Results: After 8 weeks of diabetes, sciatic blood flow was 50 % reduced. Two weeks of WAY151 003 (3 or 100 mg/kg) treatment completely corrected this deficit and chelerythrine dose-dependently improved nerve perfusion. The inhibitors dose-dependently corrected a 20 % diabetic motor conduction deficit, however, at high doses ( > 3.0 mg/kg WAY151003; > 0.1 mg/kg chelerythrine) conduction velocity was reduced towards the diabetic level. Sciatic Na(+),K(+)-ATPase activity, 42 % reduced by diabetes, was partially corrected by low but not high dose WAY151 003. In contrast, only a very high dose of chelerythrine partially restored Na(+),K(+)-ATPase activity. A 30 % diabetic deficit in sciatic glutathione content was unchanged by protein kinase C inhibition. The benefits of WAY151 003 on blood flow and conduction velocity were blocked by nitric oxide synthase inhibitor co-treatment.<br />Conclusion/interpretation: Protein kinase C contributes to experimental diabetic neuropathy by a neurovascular mechanism rather than through Na(+),K(+)-ATPase defects.
- Subjects :
- Alkaloids
Animals
Benzophenanthridines
Diabetes Mellitus, Experimental metabolism
Diabetic Neuropathies drug therapy
Enzyme Inhibitors pharmacology
Male
Neural Conduction drug effects
Neural Conduction physiology
Protein Kinase C antagonists & inhibitors
Rats
Rats, Sprague-Dawley
Regional Blood Flow drug effects
Sciatic Nerve blood supply
Sciatic Nerve drug effects
Diabetes Mellitus, Experimental physiopathology
Diabetic Neuropathies physiopathology
Phenanthridines pharmacology
Piperidines pharmacology
Protein Kinase C metabolism
Sciatic Nerve physiopathology
Sodium-Potassium-Exchanging ATPase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0012-186X
- Volume :
- 42
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Diabetologia
- Publication Type :
- Academic Journal
- Accession number :
- 10447525
- Full Text :
- https://doi.org/10.1007/s001250051280