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-peptides enhance vasoconstriction in cerebral
circulation
1 Center for Clinical and Molecular Neurobiology, Department of Neurology, and 2 Division of Pulmonary Critical Care, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota 55455; and 3 McLaughlin Research Institute, Great Falls, Montana 59405
Amyloid-
(A)-peptides are involved in the
pathophysiology of Alzheimer's dementia. We studied the effects of
A 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 A1-40 (0.1-10 µM), but
not with the reverse peptide A40-1, reduced resting CBF
(
29 ± 4% at 5 µM; P < 0.05) and augmented
the reduction in CBF produced by the thromboxane analog U-46619
(+45 ± 3% at 5 µM; P < 0.05). A1-40
or A1-42 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 to produce free radicals, abolished its vascular effects. Nanomolar concentrations of
A1-40 constricted isolated pressurized middle cerebral artery
segments with intrinsic tone (16 ± 3% at 100 nM;
P < 0.05). We conclude that A acts directly on
cerebral arteries to produce vasoconstriction and to enhance selected
constrictor responses. The evidence supports the idea that A-induced
production of reactive oxygen species plays a role in this effect. The
vascular actions of A may contribute to the deleterious effects
resulting from accumulation of this peptide in Alzheimer's dementia.
Alzheimer's disease; cerebral blood flow; reactive oxygen species; laser Doppler flowmetry
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