ATP-sensitive K(+) channel effects on nerve function, Na(+), K(+) ATPase, and glutathione in diabetic rats.
Some vasodilators correct nerve conduction velocity and endoneurial blood flow deficits in diabetic rats. It is not known whether vasa nervorum has ATP-sensitive K(+) (K(ATP)) channels that mediate vasodilation, or whether K(ATP) channels could modulate peripheral nerve function. Therefore, we examined the effects of 2 weeks treatment with the K(ATP) channel openers, celikalim and WAY135201 (R-4-[3, 4-dioxo-2-(1, 2, 2-trimethyl-propylamino)-cyclobut-1-1-enylamino]-3-methoxy-+ ++benzonitri le), on sciatic nerve blood flow, conduction velocity, Na(+)-K(+) ATPase activity and glutathione content after 6 weeks of untreated streptozotocin-diabetes in rats. Blood flow and motor conduction velocity, 47.6% and 20.3% reduced by diabetes, respectively, were completely restored by both celikalim and WAY135201 treatments. Diabetes diminished sciatic Na(+)-K(+) ATPase activity by 47.6% and this was 80-90% corrected by the K(ATP) channel openers. Sciatic nerve glutathione content, 30.3% reduced by diabetes, was unaffected by celikalim or WAY135201. Thus, K(ATP) channel openers had marked beneficial effects on nerve perfusion and function in experimental diabetic neuropathy, and may be suitable for further study in clinical trials.
Hohman
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Wyeth-Ayerst Research, 09543-8000, Princeton, NJ, USA.
Cotter
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Cameron
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D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D001783:Blood Flow Velocity / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D005978:Glutathione / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects* / Q000378:metabolism
D000840:Anisoles; D001578:Benzopyrans; D001786:Blood Glucose; D007211:Indoles; D015221:Potassium Channels; C411944:WAY135201; C067406:WAY 120491; D000255:Adenosine Triphosphate; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione