Amyloid β-(1–40) stimulates cyclic GMP production via release of kinins in primary cultured endothelial cells

• Published in: European journal of pharmacology 1999-10, Vol.382 (1), p.27-33
• Main Authors: Wirth, Klaus J., Fink, Edwin, Rudolphi, Karl, Heitsch, Holger, Deutschländer, Norbert, Wiemer, Gabriele
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid beta-Peptides - pharmacology; Amyloid beta-Peptides - physiology; Amyloid β-(1–40); Animals; Aorta - cytology; Aorta - drug effects; Aorta - ultrastructure; Biological and medical sciences; Bradykinin; Bradykinin - analogs & derivatives; Bradykinin - pharmacology; Bradykinin Receptor Antagonists; Cattle; Cells, Cultured; cGMP; Coronary Vessels - cytology; Coronary Vessels - drug effects; Coronary Vessels - ultrastructure; Coumarins - pharmacology; Cyclic GMP - biosynthesis; Endothelial cells cultured; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - ultrastructure; Enzyme Inhibitors - pharmacology; Kallikreins - antagonists & inhibitors; Kinins - metabolism; Medical sciences; Microcirculation - drug effects; Microscopy, Electron; Neurology; Nitric Oxide Synthase - antagonists & inhibitors; Nitroarginine - pharmacology; Peptide Fragments - pharmacology; Peptide Fragments - physiology; Rats; Serine Proteinase Inhibitors - pharmacology; Vascular diseases and vascular malformations of the nervous system; Vasoactivity
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(99)00576-2

Increased β-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 vessel wall leading to cerebral amyloid angiopathy. Freshly solubilised amyloid β-(1–40) was previously reported to exert a vasoconstrictor effect. We investigated whether amyloid β-(1–40) affects the nitric oxide (NO)/cyclic GMP pathway in primary cultured endothelial cells from bovine aorta and rat coronary microvessels. Surprisingly, a significant increase in cyclic GMP production after incubation with freshly dissolved amyloid β-(1–40) was found. The stimulation of cyclic GMP production could be inhibited by the bradykinin B 2 receptor antagonist icatibant, the NO synthase inhibitor N-ω-nitro- l-arginine, the serine protease inhibitor 3,4-dichloroisocoumarin and the selective plasma kallikrein inhibitor Pefabloc PK, suggesting activation of the plasma kallikrein–kinin system. This is supported by a three- to four-fold increase in kinins in the supernatant of both types of endothelial cells after incubation with amyloid β-(1–40) at concentrations of 10 −7 and 10 −6 mol/l.