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

Abstract

Amyloid angiopathy is characterized by amyloid ft-peptide (Aft) 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 Aft on normal fibroblast K+ channels and prevention of Aft-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 Aft. 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 Aft (10~6 M), or pre-treatment with KCOs before the addition of ft-amyloid. Vessels treated with Aft exhibited features of endothelial dysfunction: enhanced vasoconstriction and diminished endothelium- dependent vasodilation. Pre-treatment with KCOs significantly antagonized the Aft effect in both cerebral and aortic vessel segments. This protection was provided by both KC3 and KATP channel openers. Endothelial damage by Aft 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 Aft induced endothelial dysfunction and that KCOs may have a role in the treatment of degenerative cerebrovascular disease as seen in stroke, AD and aging. [Neurol Res 1999; 21: 345-351]