Zacopride selectively activates the Kir2.1 channel via a PKA signaling pathway in rat cardiomyocytes

Zhang, Li; Liu, Qinghua; Liu, ChengFang; Zhai, Xuwen; Feng, Qi; Xu, Ruiling; Cui, Xiangli; Zhao, Zhi‐Qing; Cao, Ji‐Min; Wu, Bo-Wei

doi:10.1007/s11427-013-4531-z

Cited by 18 publications

(16 citation statements)

References 24 publications

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“…Consistently, our current data demonstrate the ability of zacopride to eliminate the ex-vivo triggered arrhythmia in muscles from both non-failing and failing human hearts in a concentration-dependent manner, with an effective IC 50 in the range of 28 to 40 µmol/L. In line with these effective high zacopride concentrations, a previous study showed that mandatory zacopride concentration to attain a maximal efficacy for the I K1 activation is greatly elevated in human embryonic kidney-293 cells (100 µmol/L) [37] compared to rat ventricular myocytes (1 µmol/L) [15]. Moreover, zacopride (at the highest applicable concentration, 200 µmol/L) did not affect isoproterenol-induced cardiac contractile changes, including Fdev, TTP, RT50 and RT90 in the majority of failing heart muscles, which were not susceptible to the arrhythmogenic effect of isoproterenol/caffeine combination.…”

Section: Discussionmentioning

confidence: 84%

“…Zacopride is a moderate I K1 channel stimulator that selectively amplifies the I K1 current up to 40%, through the activation of the Kir2.1 homomeric channel via a PKA-dependent pathway [15, 37]. This modest enhancement in I K1 is different from that induced by the I K1 channel gene-transfer strategy, where the I K1 is increased by more than 100%, which makes zacopride a promising antiarrhythmic candidate [9, 15].…”

Section: Discussionmentioning

confidence: 99%

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Effects of zacopride, a moderate IK1 channel agonist, on triggered arrhythmia and contractility in human ventricular myocardium

Elnakish¹,

Canan

Kilic

et al. 2017

Pharmacological Research

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Ventricular tachycardia is the leading cause of sudden arrhythmic death in the U.S. Recently, the moderate IK1 channel activator, zacopride, was shown to suppress triggered ventricular tachycardia in rats. Nonetheless, concerns were raised about the possibility of pro-arrhythmic activity after IK1 channel stimulation based on the promising anti-arrhythmic strategy of IK1 blockade in other animal models. Therefore, the goal of the current study was to investigate the ex-vivo effects of zacopride on triggered arrhythmia and contractility in ventricular human myocardium in order to validate data that was solely obtained from animal models. Application of 100 nmol/L isoproterenol and 0.5 mmol/L caffeine led to triggered arrhythmia in isolated cardiac muscles from non-failing and end-stage failing hearts. However, the occurrence of arrhythmia in muscles of non-failing hearts was markedly higher than those of end-stage failing hearts. Interestingly, zacopride eliminated the ex-vivo triggered arrhythmia in these muscles of non-failing and failing hearts in a concentration-dependent manner, with an effective IC50 in the range of 28 to 40 µmol/L. Conversely, in the absence of isoproterenol/caffeine, zacopride led to a negative inotropic effect in a concentration-dependent manner. Reduced cardiac contraction was clearly observed at high zacopride concentration of 200 µmol/L, along with the occurrence of contractile alternans in muscles of non-failing and failing hearts. Zacopride shows promising antiarrhythmic effects against triggered arrhythmia in ventricular human myocardium. However, in the absence of Ca2+ overload/arrhythmia, zacopride, albeit at high concentrations, decreases the force of contraction and increases the likelihood of occurrence of contractile alternans, which may predispose the heart to contractile dysfunction and/or arrhythmia. Overall, our results represent a key step in translating this drug from the benchtop to the bedside in the research area.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Effects of zacopride, a moderate IK1 channel agonist, on triggered arrhythmia and contractility in human ventricular myocardium

Elnakish¹,

Canan

Kilic

et al. 2017

Pharmacological Research

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“…However, the specificity of ZAC in stimulating a direct signaling link between mTOR-p70S6K and cardiac repair through the IK1 channel needs to be further addressed using either the rapamycin to specifically inhibit mTOR activation or the mTOR-knockout model. Given the fact that the IK1 channel has been reported with suppression of ventricular arrhythmias [7,8] and augmentation of cardiac function as shown in the present study, pharmacological stimulation of the IK1 channel may open another 'window of opportunity' in the treatment of patient with heart failure.…”

Section: +mentioning

confidence: 64%

“…Myocardial hypertrophy has been associated with both ventricular and supraventricular arrhythmias. We have previously reported that ZAC-inhibited ventricular arrhythmias is blocked by protein kinase A (PKA) inhibitor, but is not altered by protein kinase C (PKC) and protein kinase G (PKG) blockers [8]. However, it is necessary to further address whether ZAC promotedcardiac repair is associated with modulation of protein kinases.…”

Section: +mentioning

confidence: 99%

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Opening of the inward rectifier potassium channel alleviates maladaptive tissue repair following myocardial infarction

Liu¹,

Liu²,

Luo³

et al. 2016

ABBS

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Activation of the inward rectifier potassium current (IK1) channel has been reported to be associated with suppression of ventricular arrhythmias. In this study, we tested the hypothesis that opening of the IK1 channel with zacopride (ZAC) was involved in the modulation of tissue repair after myocardial infarction. Sprague-Dawley rats were subject to coronary artery ligation and ZAC was administered intraperitoneally (15 µg/kg/day) for 28 days. Compared with the ischemia group, treatment with ZAC significantly reduced the ratio of heart/body weight and the cross-sectional area of cardiomyocytes, suggesting less cardiac hypertrophy. ZAC reduced the accumulation of collagen types I and III, accompanied with decrease of collagen area, which were associated with a reduction of collagen deposition in the fibrotic myocardium. Echocardiography showed improved cardiac function, evidenced by the reduced left ventricular end-diastolic dimension and left ventricular end-systolic dimension, and the increased ejection fraction and fractional shortening in ZAC-treated animals (all P < 0.05 vs. ischemia group). In coincidence with these changes, ZAC upregulated the protein level of the IK1 channel and down-regulated the phosphorylation of mammalian target of rapamycin (mTOR) and 70-kDa ribosomal protein S6 (p70S6) kinase. Administration of chloroquine alone, an IK1 channel antagonist, had no effect on all the parameters measured, but significantly blocked the beneficial effects of ZAC on cardiac repair. In conclusion, opening of the IK1 channel with ZAC inhibits maladaptive tissue repair and improves cardiac function, potentially mediated by the inhibition of ischemia-activated mTOR-p70S6 signaling pathway via the IK1 channel. So the development of pharmacological agents specifically targeting the activation of the IK1 channel may protect the heart against myocardial ischemia-induced cardiac dysfunction.

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Beta‐Cell Ion Channels and Their Role in Regulating Insulin Secretion

Thompson

Satin

2021

Comprehensive Physiology

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Beta cells of the pancreatic islet express many different types of ion channels. These channels reside in the β-cell plasma membrane as well as subcellular organelles and their coordinated activity and sensitivity to metabolism regulate glucose-dependent insulin secretion. Here, we review the molecular nature, expression patterns, and functional roles of many β-cell channels, with an eye toward explaining the ionic basis of glucose-induced insulin secretion. Our primary focus is on K ATP and voltage-gated Ca 2+ channels as these primarily regulate insulin secretion; other channels in our view primarily help to sculpt the electrical patterns generated by activated β-cells or indirectly regulate metabolism. Lastly, we discuss why understanding the physiological roles played by ion channels is important for understanding the secretory defects that occur in type 2 diabetes.

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Zacopride selectively activates the Kir2.1 channel via a PKA signaling pathway in rat cardiomyocytes

Cited by 18 publications

References 24 publications

Effects of zacopride, a moderate IK1 channel agonist, on triggered arrhythmia and contractility in human ventricular myocardium

Effects of zacopride, a moderate IK1 channel agonist, on triggered arrhythmia and contractility in human ventricular myocardium

Opening of the inward rectifier potassium channel alleviates maladaptive tissue repair following myocardial infarction

Beta‐Cell Ion Channels and Their Role in Regulating Insulin Secretion

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