The protective effect of K+ channel openers on beta-amyloid induced cerebrovascular endothelial dysfunction

Amyloid angiopathy is characterized by amyloid beta-peptide (A beta) deposi tion and may contribute to the cerebrovascular abnormalities that precede t he onset of Alzheimer's Disease (AD). That aberrant potassium (K+) channel function occurs in AD patients is supported by deleterious effects of A bet a on normal fibroblast K+ channels and prevention of A beta-induced toxicit y by potassium channel openers (KCOs) in neuronal cell culture. We report h ere that KCOs protect cerebral and peripheral vessels against the endotheli al damage induced by A beta. Pressurized posterior cerebral artery and aort ic ring segments from the rat were constricted and then relaxed with the en dothelium-dependent vasodilator acetylcholine before and after incubation w ith A beta (10(-6) M), or pre-treatment with KCOs before the addition of be ta-amyloid. Vessels treated with A beta exhibited features of endothelial d ysfunction: 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 pro vided by both K-Ca and K-ATP 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 th at potassium channel openers protect against A beta induced endothelial dys function and that KCOs may have a role in the treatment of degenerative cer ebrovascular disease as seen in stroke, AD and aging.