Amyloid beta-(1-40) stimulates cyclic GMP production via release of kininsin primary cultured endothelial cells

Increased beta-amyloid production is believed to play a central role in the pathogenesis of Alzheimer's disease. Amyloid is deposited not only in the brain of Alzheimer patients as senile plaques but also in the cerebral vess el wall leading to cerebral amyloid angiopathy. Freshly solubilised amyloid beta-(1-40) was previously reported to exert a vasoconstrictor effect. We investigated whether amyloid beta-(1-40) affects the nitric oxide (NO)/cycl ic GMP pathway in primary cultured endothelial cells from bovine aorta and rat coronary microvessels. Surprisingly, a significant increase in cyclic G MP production after incubation with freshly dissolved amyloid beta-(1-40) w as found. The stimulation of cyclic GMP production could be inhibited by th e bradykinin B-2 receptor antagonist icatibant, the NO synthase inhibitor N -omega-nitro-1-arginine, the serine protease inhibitor 3,4-dichloroisocouma rin and the selective plasma kallikrein inhibitor Pefabloc PK, suggesting a ctivation of the plasma kallikrein-kinin system. This is supported by a thr ee- to four-fold increase in kinins in the supernatant of both types of end othelial cells after incubation with amyloid beta-(1-40) at concentrations of 10(-7) and 10(-6) mol/l. (C) 1999 Elsevier Science B.V. All rights reser ved.