A beta-peptides enhance vasoconstriction in cerebral circulation.
Amyloid-beta (A beta)-peptides are involved in the pathophysiology of Alzheimer's dementia. We studied the effects of A beta on selected constrictor responses of cerebral circulation. Mice were anesthetized (by using urethane-chloralose) and equipped with a cranial window. Arterial pressure and blood gases were monitored and controlled. Cerebral blood flow (CBF) was monitored by a laser Doppler probe. Topical superfusion with A beta 1-40 (0.1-10 microM), but not with the reverse peptide A beta 40-1, reduced resting CBF (-29 +/- 4% at 5 microM; P < 0.05) and augmented the reduction in CBF produced by the thromboxane analog U-46619 (+45 +/- 3% at 5 microM; P < 0.05). A beta 1-40 or A beta 1-42 did not affect the reduction in CBF produced by hypocapnia. The reduction in resting CBF and the enhancement of vasoconstriction were reversed by treatment with the free radical scavengers superoxide dismutase or manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin. Substitution of the methionine residue in position 35 with norleucine, a mutation that abolishes the ability of A beta to produce free radicals, abolished its vascular effects. Nanomolar concentrations of A beta 1-40 constricted isolated pressurized middle cerebral artery segments with intrinsic tone (-16 +/- 3% at 100 nM; P < 0.05). We conclude that A beta acts directly on cerebral arteries to produce vasoconstriction and to enhance selected constrictor responses. The evidence supports the idea that A beta-induced production of reactive oxygen species plays a role in this effect. The vascular actions of A beta may contribute to the deleterious effects resulting from accumulation of this peptide in Alzheimer's dementia.
Niwa
K
K
Center for Clinical and Molecular Neurobiology, Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Porter
V A
VA
Kazama
K
K
Cornfield
D
D
Carlson
G A
GA
Iadecola
C
C
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000544:Alzheimer Disease / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D016166:Free Radical Scavengers / Q000494:pharmacology; D016857:Hypocapnia / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013482:Superoxide Dismutase