Dofetilide Enhances the Contractility of Rat Ventricular Myocytes via Augmentation of Na+–Ca2+ Exchange

Zhang, Xuanping; Wu, Bo-Wei; Yang, Cheng-Ao; Wang, Jie; Niu, Shuan-Cheng; Zhang, Mingsheng

doi:10.1007/s10557-009-6163-x

Cited by 14 publications

(9 citation statements)

References 35 publications

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“…Dofetilide is a relatively pure I Kr /hERG blocker at the concentrations tested (Table 1) although it has recently been suggested that it can also enhance Na/Ca exchange (Antoons and Sipido, 2009;Zhang et al, 2009). In the present embryo culture study, dofetilide caused a concentration-dependent slowing of the embryonic heart and irregular inter-beat times/arrhythmia for both the atria and ventricles.…”

Section: Potassium Channelsmentioning

confidence: 49%

The effect of drugs with ion channel‐blocking activity on the early embryonic rat heart

Abela

Ritchie

Ababneh

et al. 2010

Birth Defects Research Pt B

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This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the I(Kr)/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or I(Kr)/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing.

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Section: Potassium Channelsmentioning

confidence: 49%

The effect of drugs with ion channel‐blocking activity on the early embryonic rat heart

Abela

Ritchie

Ababneh

et al. 2010

Birth Defects Research Pt B

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“…Dofetilide increased the amplitude of DADs induced by cardiac glycoside acetyl-strophanthidin in isolated cardiac Purkinje fibers using microelectrode techniques [64]. Dofetilide dose-dependently increased I NCX1 with EC 50 values of 0.149 μM and 0.249 μM for the inward and outward components, respectively, in rat cardiac ventricular myocytes [65]. However, there has been no report on the molecular mechanisms of activation of I NCX1 by dofetilide.…”

Section: Dofetilidementioning

confidence: 99%

Cardiac Na+/Ca2+ exchange stimulators among cardioprotective drugs

Watanabe

2019

J Physiol Sci

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We previously reviewed our study of the pharmacological properties of cardiac Na + /Ca 2+ exchange (NCX1) inhibitors among cardioprotective drugs, such as amiodarone, bepridil, dronedarone, cibenzoline, azimilide, aprindine, and benzyl-oxyphenyl derivatives (Watanabe et al. in J Pharmacol Sci 102:7-16, 2006). Since then we have continued our studies further and found that some cardioprotective drugs are NCX1 stimulators. Cardiac Na + /Ca 2+ exchange current (I NCX1) was stimulated by nicorandil (a hybrid ATP-sensitive K + channel opener), pinacidil (a non-selective ATP-sensitive K + channel opener), flecainide (an antiarrhythmic drug), and sodium nitroprusside (SNP) (an NO donor). Sildenafil (a phosphodiesterase-5 inhibitor) further increased the pinacidil-induced augmentation of I NCX1. In paper, here I review the NCX stimulants that enhance NCX function among the cardioprotective agents we examined such as nicorandil, pinacidil, SNP, sildenafil and flecainide, in addition to atrial natriuretic (ANP) and dofetilide, which were reported by other investigators. Keywords Cardiac Na + /Ca 2+ exchanger (NCX1) • Cardiac Na + /Ca 2+ exchange current (I NCX1) • NCX1 stimulator • Patchclamp method • Cardioprotective drug

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“…The study by Zhang et al in the current issue questions this specificity of dofetilide [1]. The authors found a potentiating effect of the drug on the NCX current, I NCX , in myocytes from adult rat hearts.…”

Section: Introductionmentioning

confidence: 79%

“…KB-R7943 is not as highly specific as some of the newer NCX inhibitors [17] and in the intact myocyte experiments (Fig. 3 in the study by Zang et al [1]), its effect could as well correspond to a reduction of Ca current. In the next data set though (Fig.…”

Section: Does An Increase In Ncx Activity Have a Positive Inotropic Amentioning

confidence: 84%

“…The paper by Zhang et al in this issue [1] is challenging some well established concepts regarding the actions of dofetilide and adds a new dimension to the discussion of whether we can/should target the Na/Ca exchanger (NCX) in treatment of heart failure. It therefore deserves some further scrutiny and needs to be discussed in a broad perspective.…”

Section: Introductionmentioning

confidence: 99%

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Dofetilide as Activator of Na/Ca Exchange: New Perspectives on an ‘Old’ Drug

Antoons

Sipido

2009

Cardiovasc Drugs Ther

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Dofetilide Enhances the Contractility of Rat Ventricular Myocytes via Augmentation of Na+–Ca2+ Exchange

Abstract: We conclude that DOF enhanced contractility of rat ventricular myocytes. The enhancement of NCE may be involved in the positive inotropic action of DOF.

Cited by 14 publications

References 35 publications

The effect of drugs with ion channel‐blocking activity on the early embryonic rat heart

The effect of drugs with ion channel‐blocking activity on the early embryonic rat heart

Cardiac Na+/Ca2+ exchange stimulators among cardioprotective drugs

Dofetilide as Activator of Na/Ca Exchange: New Perspectives on an ‘Old’ Drug

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