The amyloid-beta (Abeta) peptide has been linked to the pathology of Alzheimer's disease (AD). There is now evidence to support a vasoconstrictive effect of Abeta protein that could be detected in peripheral skin microvasculature. In this study we investigated the ability of acetylcholinesterase (AChE) inhibitors, Donepezil and Rivastigmine, to modulate the vasoconstrictor activity of Abeta25-35 and Abeta1-40. The ability of these drugs to improve endothelial mediated vascular responses to acetylcholine and bradykinin subsequent to perfusion of Abeta peptides was also investigated. The vascular responses to Abeta peptides, acetylcholine, bradykinin and sodium nitroprusside and their modulation by acetylcholinesterase inhibitors were examined in the base of a vacuum induced blister raised on the rat hind footpad using laser Doppler flowmetry. Abeta25-35 (1 microM) and Abeta1-40 (0.1 microM) induced a vasoconstrictor effect and significantly reduced the vasodilator response to acetylcholine (100 microM) and bradykinin (1 microM). Donepezil (100 microM) and Rivastigmine (100 microM) both reduced the vasoconstrictor effect of Abeta peptides, and significantly restored the endothelial vascular response to acetylcholine. Similarly, Donepezil significantly restored the endothelial vascular response to bradykinin. The results also showed that the actions of acetylcholinesterase inhibitors are independent of a direct action on smooth muscle cell reactivity or on endothelial cell function in the absence of Abeta. The current study provides the first evidence in vivo to suggest that acetylcholinesterase inhibitors modulate the vasoconstrictive effects of Abeta peptides at the level of skin microvasculature. We raise the notion that Donepezil and Rivastigmine mediate these vascular modulatory effects via an action on Abeta-mediated vasoconstrictor mechanisms rather than an independent action on endothelial or smooth muscle cell mediated responses.