Amyloid beta-(1-40) stimulates cyclic GMP production via release of kinins in 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 vessel 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)/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 beta-(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-omega-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 beta-(1-40) at concentrations of 10(-7) and 10(-6) mol/l.
Wirth
K J
KJ
Hoechst Marion Roussel Deutschland, DG Cardiovascular Diseases, H 813, Industriepark Höchst, D-65926, Frankfurt am Main, Germany. klaus.wirth@hmrag.com
Fink
E
E
Rudolphi
K
K
Heitsch
H
H
Deutschländer
N
N
Wiemer
G
G
D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D002417:Cattle; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D003374:Coumarins / Q000494:pharmacology; D006152:Cyclic GMP / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049934:Isocoumarins; D007610:Kallikreins / Q000037:antagonists & inhibitors; D007705:Kinins / Q000378:metabolism*; D008833:Microcirculation / Q000187:drug effects; D008854:Microscopy, Electron; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology* / Q000502:physiology; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D065168:Bradykinin Receptor Antagonists; D003374:Coumarins; D004791:Enzyme Inhibitors; D049934:Isocoumarins; D007705:Kinins; D010446:Peptide Fragments; D015842:Serine Proteinase Inhibitors; C078592:amyloid beta-protein (1-40); D019335:Nitroarginine; C046235:3,4-dichloroisocoumarin; C065679:icatibant; D019001:Nitric Oxide Synthase; D007610:Kallikreins; D006152:Cyclic GMP; D001920:Bradykinin