Activation of muscarinic K+ channels by arecaidine propargyl ester in isolated guinea-pig atrial myocytes

Abstract

Arecaidine propargyl ester (APE) was developed as a potential candidate compound for the treatment of Alzheimer's disease. APE has been shown to have cardiovascular effects. APE produces negative chronotropic and inotropic effects in isolated atria. However, the ionic mechanisms underlying the cardiovascular effects of APE in guinea-pig atria are unclear. The aims of this study were: (1) to examine the shortening effect of APE on action potential duration (APD) and to compare the difference in potency between APE and muscarine in isolated single guinea-pig atrial myocytes by using the current clamp method, (2) to examine by using patch clamp techniques the ionic mechanisms underlying the cardiac effects of APE, and (3) to determine whether the cardiac effects caused by APE affect the usefulness of APE as a potential candidate for the treatment of Alzheimer's disease. The APE significantly reduced the APD in guinea-pig atria and produced no direct effect on ventricular myocytes. APE is approximately 20 times as potent as muscarine in shortening the APD. Attenuation of the APD was consistently accompanied by a hyperpolarization of the resting membrane potential in a concentration-dependent manner. The APE activated muscarinic K+ channels and increased potassium conductance in guinea-pig atrial myocytes. In the cell-attached configuration, the APE contained in the pipette increased the channel-opening probability and decreased the closed-state time interval. The proposal that APE can be used as a potential remedy for the treatment of Alzheimer's disease should be taken into consideration the undesirable cardiovascular side effects that APE causes at lower concentrations.

Arecoline inhibits intermediate-conductance calcium-activated potassium channels in human glioblastoma cell lines

“…The activity of fibroblast or prostatic IK Ca channels has been reported to be potentially important in cell growth through a delicate control of Ca 2 þ entry (Peña andRane, 1999, Lai et al, 2007;Lallet-Daher et al, 2009;Ohya et al, 2011). A number of studies have revealed that ARE could stimulate the production of connective-tissue growth factor in buccal fibroblasts and influence the functions of neutrophils, lymphocytes or macrophages (Hung et al, 2000;Lai et al, 2007;Shen et al, 2007;Deng et al, 2009;Chen andChang, 2012, Hwang et al, 2013;Grossinger et al, 2014;Xu et al, 2014). Therefore, to what extent ARE-induced block of IK Ca channels observed in the present study is capable of exerting its adverse effects on the activity of oral keratinocytes remains to be further investigated.…”

“…Reports showed that glioma cells possess M2 muscarinic receptors, activation by acetylcholine could stimulate small-conductance Ca 2þ -activated K þ (SK Ca ) channels in neocortical pyramidal neurons (Brombas et al, 2014;Ferretti et al, 2012Ferretti et al, , 2013. ARE has been shown to suppress ether-à-gogo-related K þ current and stimulate muscarinic-K þ channels or ATPsensitive K þ channels (Chen, 2005;Yoshizumi et al, 2008;Ling et al, 2012;Zhao et al, 2012). However, whether this compound directly interacts with ion channels to perturb ion currents and change membrane potential remains largely unexplored.…”

Biomedical Vignette

“…However, APE has been shown to produce negative chronotropic and ionotropic effects in isolated atria [29]. In this communication, Chen [30] showed that APE activated muscarinic K + channels and increased potassium conductance in guinea-pig atrial myocytes. In addition, APE also shortened action potential duration in the same system.…”