Antihypertensive Antagonists of L-Type Calcium Channel Exert Enhancement of Alzheimer's Aβ Peptides Effect on Cells

Abstract

The Alzheimer's Aβ peptides are shown to increase the cytosolic calcium concentrations of cells in culture. Such an alteration may cause a variety of secondary effects, leading to cell degeneration and reduced cell culture growth. Cytosolic calcium concentration can be increased by the formation of cation-selective ion channels by the Aβ peptides. This property is well documented and has been extensively studied both in artificial membrane systems as well as in living cells. Here we show that L-type calcium channel antagonists, commonly used in the treatment of hypertension and ischemic heart disease, intensify the capacity of Aβ peptides to increase cytosolic calcium concentrations and consequently enhance the cytotoxicity of the Aβ peptides. Calcium imaging experiments were conducted with the fluorescent indicator Fura-2 to measure at different periods of times the levels of cytosolic calcium during exposure to Aβ peptides and to the L-type calcium channel antagonists. Two different 1,4-dihydropyridines (nifedipine, and nitrendipine), and Diltiazem, a structurally unrelated Ca2+-channel antagonist belonging to the phenylalkylamine class were used and found to exert significant excitatory effects on the toxicity of Aβ. The reduced toxicity observed in solutions of combinations of Aβ40 and Aβ42 is also reversed by L-type calcium channel antagonists. The toxicity of Aβ peptides was weighed by quantifying the growth of cultures of PC12 cells using the colorimetric assay XTT and by measuring the release of LDH to the media. The enhancement of the Aβ peptides toxicity by L-type calcium channel antagonists can be constrained by specific Aβ ion channel blockers suggesting the mediation of the ion channel property of Aβ peptides. The relevance of our finding derives from the widespread clinical use of L-type calcium channel antagonists in the treatment of hypertension and angina pectoris.