On the Risk Concerns of Zacopride, a Moderate IK1 Channel Agonist With Cardiac Protective Action

Wu, Bo-Wei; Cao, Ji‐Min

doi:10.1097/fjc.0000000000000148

Cited by 2 publications

(6 citation statements)

References 21 publications

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“…Indeed, humans exhibit lower repolarization reserve contributions from I K1 and I Ks compared to animals, confirming species-specific determinants of repolarization and limitations of animal models for human diseases [18]. Consequently, it has been concluded that the effects of the I K1 channel agonists on heart rhythm/arrhythmias may potentially be coupled with the type of arrhythmia and species, with the need for further future investigation in humans [9, 15]. …”

Section: Introductionmentioning

confidence: 95%

“…Yet, when the I K1 current reduction augments membrane resistance, a specified depolarizing membrane current could lead to a great extent of voltage deflection. This finding could signify a key mechanism for the occurrence of DADs-induced arrhythmias [9]. In cardiomyocytes from failing rat hearts, enhanced Ca 2+ release through RyR2 has been reported to inhibit I K1 , signifying a substrate for VT in heart failure (HF) [10].…”

Section: Introductionmentioning

confidence: 99%

“…Hence, an anti-arrhythmic approach should augment the I K1 to get it back to a near-normal condition. As previously noted, an ideal agent for the treatment of VT may be a drug that enhances the opening of K + channels at the RP but not at the AP peak, which means a drug that augments the I K1 current activation [9, 14]. However, the lack of I K1 -specific pharmacological tools, in particular a specific agonist, was a major constraint to further investigate I K1 in the past [14].…”

Section: Introductionmentioning

confidence: 99%

“…Zacopride was originally reported as a potent antagonist of 5-hydroxytryptamine (5-HT) 3 and an agonist of 5-HT 4 receptors that has been experimentally used as an anti-emetic, gastroprokinetic, and anxiolytic agent [9]. Zacopride has been reported to selectively activate the I K1 channel in rat ventricular myocytes, moderately enhance the I K1 current, hyperpolarize the RP, and decrease the APD exclusive of affecting other channels, transporters, and pumps, with subsequent suppression of triggered VT in rats [15].…”

Section: Introductionmentioning

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: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

show abstract

“…ZAC shortens the duration of the action potential and hyperpolarizes the resting membrane potential by moderately increasing the current density of the IK1. In the in vivo models, it has also been found that ZAC suppresses aconitine-triggered or infarction-induced ventricular arrhythmias [7,9].…”

Section: Introductionmentioning

confidence: 99%

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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On the Risk Concerns of Zacopride, a Moderate IK1 Channel Agonist With Cardiac Protective Action

Cited by 2 publications

References 21 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

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