title: Statins prevent beta-amyloid inhibition of sympathetic alpha7-nAChR-mediated nitrergic neurogenic dilation in porcine basilar arteries.
abstract: The exact mechanism underlying regional cerebral hypoperfusion in the early phase of Alzheimer's disease (AD) is not understood. We have shown in isolated porcine cerebral arteries that stimulation of sympathetic alpha7-nicotinic acetylcholine receptors (alpha7-nAChRs) causes release of nitric oxide in parasympathetic nitrergic nerves and vasodilation. We therefore examined if beta-amyloid peptides (Abetas), which play a key role in pathogenesis of AD, blocked sympathetic alpha7-nAChRs leading to reduced neurogenic nitrergic dilation in isolated porcine basilar arteries, using in vitro tissue bath, calcium image, and patch clamping techniques. The results indicated that Abeta(1-40), but not Abeta(40-1), blocked relaxation of endothelium-denuded basilar arterial rings induced by nicotine (100 micromol/L) and choline (1 mmol/L) without affecting that induced by sodium nitroprusside or isoproterenol. In cultured superior cervical ganglion (SCG) cells, Abeta(1-40), but not Abeta(40-1), blocked choline- and nicotine-induced calcium influx and inward currents. The Abeta blockade of the nitrergic vasodilation and inward currents, but not that of calcium influx, was prevented by acute pretreatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors mevastatin and lovastatin. These results suggest that Abeta(1-40) blocks cerebral perivascular sympathetic alpha7-nAChRs, resulting in the attenuation of cerebral nitrergic neurogenic vasodilation. This effect of Abeta may be responsible in part for cerebral hypoperfusion occurred in the early phase of the AD, which may be prevented by statins most likely because of their effects independent of cholesterol lowering. Statins may offer an alternative strategy in the prevention and treatment of AD.
authors.affiliation: Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL 62794-9629, USA.
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Si
authors.forename: Chen
authors.initials: C
authors.lastname: Long
authors.forename: Ding-I
authors.initials: DI
authors.lastname: Yang
authors.forename: Mei-Fang
authors.initials: MF
authors.lastname: Chen
authors.forename: Tony Jer-Fu
authors.initials: TJ
authors.lastname: Lee
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001488:Basilar Artery / Q000294:innervation / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002794:Choline / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000502:physiology*; D017783:Superior Cervical Ganglion / Q000166:cytology; D013552:Swine; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology; D013566:Sympathomimetics / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D016229:Amyloid beta-Peptides; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018722:Nicotinic Agonists; D020030:Nitric Oxide Donors; D018697:Nootropic Agents; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D013566:Sympathomimetics; D064569:alpha7 Nicotinic Acetylcholine Receptor; C078592:amyloid beta-protein (1-40); C090308:amyloid beta-protein (40-1); D009599:Nitroprusside; C012258:mevastatin; D009569:Nitric Oxide; D009538:Nicotine; D008148:Lovastatin; D007545:Isoproterenol; D002794:Choline; D002118:Calcium