The protective effect of K+ channel openers on beta-amyloid induced cerebrovascular endothelial dysfunction.
Amyloid angiopathy is characterized by amyloid beta-peptide (A beta) deposition and may contribute to the cerebrovascular abnormalities that precede the onset of Alzheimer's Disease (AD). That aberrant potassium (K+) channel function occurs in AD patients is supported by deleterious effects of A beta on normal fibroblast K+ channels and prevention of A beta-induced toxicity by potassium channel openers (KCOs) in neuronal cell culture. We report here that KCOs protect cerebral and peripheral vessels against the endothelial damage induced by A beta. Pressurized posterior cerebral artery and aortic ring segments from the rat were constricted and then relaxed with the endothelium-dependent vasodilator acetylcholine before and after incubation with A beta (10(-6) M), or pre-treatment with KCOs before the addition of beta-amyloid. Vessels treated with A beta exhibited features of endothelial dysfunction: enhanced vasoconstriction and diminished endothelium-dependent vasodilation. Pre-treatment with KCOs significantly antagonized the A beta effect in both cerebral and aortic vessel segments. This protection was provided by both KCa and KATP channel openers. Endothelial damage by A beta and protection by KCOs was verified by electron microscopy. The K+ channel blocker, TEA, reversed the protective effect of KCO. The results suggest that potassium channel openers protect against A beta induced endothelial dysfunction and that KCOs may have a role in the treatment of degenerative cerebrovascular disease as seen in stroke, AD and aging.
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Department of Physiology and Biophysics, University of South Florida, Tampa, USA.
Sutton
E T
ET
Thomas
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Price
J M
JM
D000109:Acetylcholine / Q000378:metabolism; D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D019610:Cytoprotection / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005609:Free Radicals / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D015221:Potassium Channels / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D005609:Free Radicals; D015221:Potassium Channels; D009569:Nitric Oxide; D000109:Acetylcholine