CHARACTERISTICS OF THE IN-VITRO VASOACTIVITY OF BETA-AMYLOID PEPTIDES

The beta-amyloid (A beta(1-40)) peptide has previously been shown to e nhance phenylephrine contraction of aortic rings in vitro. We have emp loyed a novel observation, that A beta peptides enhance endothelin-l ( ET-1) contraction, to examine the relationship between vasoactivity an d potential amyloidogenicity of A beta peptides, the role played by fr ee radicals and calcium in the vasoactive mechanism, and the requireme nt of an intact endothelial layer for enhancement of vasoactivity. Rin gs of rat aortae were constricted with ET-1 before and after addition of amyloid peptide and/or other compounds, and a comparison was made b etween post-and pretreatment contractions. In this system, vessel cons triction is consistently dramatically enhanced by A beta(1-40), is enh anced less so by A beta(1-42), and is not enhanced by A beta(25-35). T he endothelium is not required for A beta vasoactivity, and calcium ch annel blockers have a greater effect than antioxidants in blocking enh ancement of vasoconstriction by A beta peptides. In contrast to A beta -induced cytotoxicity, A beta-induced vasoactivity is immediate, occur s in response to low doses of freshly solubilized peptide, and appears to be inversely related to the amyloidogenic potential of the A beta peptides. We conclude that the mechanism of A beta vasoactivity is dis tinct from that of A beta cytotoxicity. Although free radicals appear to modulate the vasoactive effects, the lack of requirement for endoth elium suggests that loss of the free radical balance (between NO and O -2(-)) may be a secondary influence on A beta enhancement of vasoconst riction. These effects of A beta on isolated vessels, and reported eff ects of A beta in cells of the vasculature, suggest that A beta-induce d disruption of vascular tone may be a factor in the pathogenesis of c erebral amyloid angiopathy and Alzheimer's disease. Although the mecha nism of enhanced vasoconstriction is unknown, it is reasonable to prop ose that in vivo contact of A beta peptides with small cerebral vessel s may increase their tendency to constrict and oppose their tendency t o relax. The subclinical ischemia resulting from this would be expecte d to up-regulate beta APP production in and around the vasculature wit h further increase in A beta formation and deposition. The disruptive and degenerative effects of such a cycle would lead to the complete de struction of cerebral vessels and consequently neuronal degeneration i n the affected areas. (C) 1998 Academic Press.