Cholinesterase Inhibitor Blockade and its Prevention by Statins of Sympathetic α7-nAChR-Mediated Cerebral Nitrergic Neurogenic Vasodilation

Abstract

Cholinesterase inhibitors (ChEIs) have been used to treat Alzheimer's disease (AD). The efficacy of these drugs, however, is less than satisfactory. The possibility that ChEIs may have effects unrelated to ChE activity, such as negatively modulate neuronal nicotinic acetylcholine receptors (nAChRs) was evaluated. Since a7-nAChRs on cerebral perivascular sympathetic neurons mediate cerebral parasympathetic-nitrergic vasodilation, effects of physostigmine, neostigmine, and galantamine on a7-nAChR-mediated dilation in isolated porcine basilar arterial rings denuded of endothelium was examined using in vitro tissue bath technique. The results indicated that these ChEIs blocked vasodilation induced by choline (0.3 mmol/L), nicotine (0.1 mmol/L), and transmural nerve stimulation (TNS). The ChEI inhibition of dilation induced by TNS but not by choline or nicotine was prevented by atropine (0.1 lmol/L) pretreatment. Furthermore, using confocal microscopy, significant calcium influx induced by choline and nicotine in cultured porcine superior cervical ganglion (SCG) cells was attenuated by ChEIs. In a7-nAChR-expressed Xenopus oocytes, nicotine-induced inward currents were attenuated by a-bungarotoxin and ChEIs. Moreover, ChEI inhibition of nicotine-and choline-induced dilation was prevented by pretreatment with mevastatin and lovastatin (10 lmol/L), which did not affect ChEI inhibition of TNS-induced relaxation. These findings suggest that ChEIs inhibit the a7-nAChRs located on postganglionic sympathetic nerve terminals of SCG origin, causing a decreased release of nitric oxide in the neighboring nitrergic nerves and cerebral vasodilation. Inhibition of a7-nAChRs leading to a potential cerebral hypoperfusion may contribute to the limitation of ChEIs and question the validity of using a ChEI alone in treating AD. The efficacy of ChEIs may be improved by concurrent use of statins.

Sympathetic α3β2-nAChRs mediate cerebral neurogenic nitrergic vasodilation in the swine

“…␣-BGTX, A␤s, and ␣-CTX IMI (a selective ␣ 7 -nAChR antagonist), however, failed to affect nicotine-induced nitrergic vasodilation in basilar arteries of the LYD pigs even when concentrations of these blockers were in the micromolar ranges, which is about 10-fold higher than the reported IC 50 value of ␣-CTX IMI in blocking ␣ 7 -nAChR-mediated inward currents (10). Furthermore, tropane and tropinone, which in high concentrations possess ␣7-nAChR agonistic activity (33,35), did not elicit vasorelaxation of isolated basilar arteries (Supplemental Fig. S3, A and B).…”

“…The bath solution, ND96, contained (in mM) 96 NaCl, 2 KCl, 1.0 MgCl 2, 1.8 CaCl2, and Two-electrode voltage clamp recording. A modified two-electrode voltage clamp recording was used in the present study (33). Two days after the injection of human ␣7, ␣3, and ␤2-subunit cRNAs, membrane currents of the oocytes were recorded in a chamber consisting of 1.3 ml cylindrical well at room temperature.…”

“…The expression of ␣7-and ␣3␤2-nAChRs on oocytes was carried out according to our previous studies (33). cDNA encoding human neuronal ␣3-and ␤2-nAChR subtypes was provided by J. McIntosh (University of Utah, Salt Lake City, UT).…”

Endogenous methyl palmitate modulates nicotinic receptor-mediated transmission in the superior cervical ganglion

“…SA, PA, and other saturated fatty acids with Ͻ20 hydrocarbon chains have been shown to potentiate ACh-induced, ␣7-nAChR-mediated inward currents, leading to facilitation of hippocampal neurotransmission (31). The postganglionic neurons/cell bodies of the rat SCG also are endowed with ␣7-nAChR (10,25,27). Whole-cell patch-clamp studies, however, demonstrated that PAME (Fig.…”

“…Nicotine (100 M), which binds ␣7-nAChR located on the rat SCG (26,27) to induce calcium influx into neurons (26,27) and generation of inward currents (10), superfused onto the SCG caused aortic relaxation with time course similar to that induced by FES of the SCG (Fig. 1H).…”