Cholinesterase inhibitor donepezil dilates cerebral parenchymal arterioles via the activation of neuronal nitric oxide synthase.
BACKGROUND
An acetylcholinesterase inhibitor donepezil currently is used to treat patients with Alzheimer disease. However, its direct effect on cerebral blood vessels has not been evaluated. The present study was designed to examine whether donepezil induces acute cerebral arteriolar dilation and whether neuronal nitric oxide synthase contributes to this vasodilator response.


METHODS
Brain slices were obtained from neuronal nitric oxide synthase knock-out or C57BL/6J strain (control) mice as well as Wistar rats. Parenchymal arterioles were monitored using videomicroscopy. During constriction to prostaglandin F2alpha (5 x 10 m), donepezil (10-10 m) or acetylcholine (10-10 m) was added. In some experiments, brain slices were treated with a nonselective or a selective nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester [10 m] and S-methyl-L-thiocitrulline [10 m], respectively). An immunohistochemical analysis was performed using antibodies for neuronal nitric oxide synthase and acetylcholinesterase.


RESULTS
Acetylcholine concentration-dependently dilated rat parenchymal arterioles, while S-methyl-L-thiocitrulline as well as N-nitro-L-arginine methyl ester completely abolished this response. Donepezil produced arteriolar dilation, which was inhibited by S-methyl-L-thiocitrulline or N-nitro-L-arginine methyl ester. Donepezil failed to induce arteriolar dilation in the brain slice from the neuronal nitric oxide synthase knock-out mice. Immunohistochemical analysis revealed spatial relationship between neuronal nitric oxide synthase and acetylcholinesterase in the arteriolar wall.


CONCLUSIONS
Donepezil produces acute vasodilation induced by a selective activation of neuronal nitric oxide synthase in the cerebral parenchymal arterioles. This agent may be capable of enhancing this enzymatic activity directly or via acetylcholinesterase existing on the arteriolar wall.
Nakahata
Katsutoshi
K
Department of Anesthesiology, Wakayama Medical University, Wakayama, Wakayama, Japan.
Kinoshita
Hiroyuki
H
Hama-Tomioka
Keiko
K
Ishida
Yuko
Y
Matsuda
Naoyuki
N
Hatakeyama
Noboru
N
Haba
Masanori
M
Kondo
Toshikazu
T
Hatano
Yoshio
Y
D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000201:enzymology; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007189:Indans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism* / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D052248:Nitric Oxide Synthase Type I