Blocking Effect of Bepridil on Na+/Ca2+ Exchange Current in Guinea Pig Cardiac Ventricular Myocytes

Watanabe, Yasuhide; Kimura, Junko

doi:10.1254/jjp.85.370

Cited by 36 publications

(25 citation statements)

References 35 publications

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“…Therefore, the antiarrhythmic drugs with potent inhibitory action on HCN4 channels should be administered to the patients with sinoatrial node dysfunction with great caution. It is noteworthy that both amiodarone and bepridil inhibit Na + /Ca 2+ exchange current, which may also affect pacemaker function (32,33).…”

Section: Discussionmentioning

confidence: 99%

Effects of Antiarrhythmic Drugs on the Hyperpolarization-Activated Cyclic Nucleotide–Gated Channel Current

et al. 2009

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Abstract. After the report of the Cardiac Arrhythmia Suppression Trial, a tabular framework of the Sicilian Gambit has been proposed to display actions of antiarrhythmic drugs on ion channels and receptors and to provide more rational pharmacotherapy of arrhythmias. However, because effects of antiarrhythmic drugs on I f have not been thoroughly examined, we used patch clamp techniques to determine the effects of various antiarrhythmic drugs on the HCN (hyperpolarization-activated cyclic nucleotide-gated) channel currents. HCN4 channels, a dominant isoform of HCN channels in the heart, were expressed in HEK293 cells. Amiodarone and bepridil potently inhibited the HCN4 channel current with IC 50 values of 4.5 and 4.9 μM, respectively, which were close to their therapeutic concentrations. The inhibitory effects of quinidine, disopyramide, cibenzoline, lidocaine, mexiletine, aprindine, propafenone, flecainide, propranolol, and verapamil on the HCN4 channel current were weak in their therapeutic concentrations, with IC 50 values of 78.3, 249, 46.8, 276, 309, 43.7, 14.3, 1700, 50.5, and 44.9 μM, respectively, suggesting that the inhibitory effects on I f would be clinically small. d,l-Sotalol hardly affected the HCN4 channel current. Information about the HCN4-channel effects of many antiarrhythmic drugs may be useful for determining the appropriate drug for treatment of various arrhythmias while minimizing adverse effects.

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Section: Discussionmentioning

confidence: 99%

Effects of Antiarrhythmic Drugs on the Hyperpolarization-Activated Cyclic Nucleotide–Gated Channel Current

et al. 2009

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“…This drug inhibits I NCX with an IC 50 value of 8.1 µM and a Hill coefficient of 1. Since trypsin from the patch-pipette attenuates the inhibitory effect of bepridil, this drug may affect the NCX from the intracellular side (12).…”

Section: Bepridilmentioning

confidence: 99%

“…50% in the absence of albumin, while it blocks I NCX by approx. 30% in the presence of 1% bovine albumin in the external solution (12). In human plasma, which has a much higher concentration of albumin, fractions of free bepridil of 2% have been reported (31).…”

Section: Bepridilmentioning

confidence: 99%

Topics on the Na+/Ca2+ Exchanger: Pharmacological Characterization of Na+/Ca2+ Exchanger Inhibitors

2006

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Abstract. Using the whole-cell voltage clamp, we examined acute effects of various agents on Na + / Ca 2+ exchange current (I NCX ) in guinea-pig cardiac ventricular cells and transfected cells. Among the antiarrhythmic drugs, amiodarone, bepridil, dronedarone, cibenzoline, azimilide, and aprindine inhibited I NCX in a concentration-dependent manner. We also investigated the effects on NCX of 2,3-buanedione monoxim (BDM) and selective NCX inhibitors such as KB-R7943, SEA0400, and SN-6. The presence of trypsin in the pipette solution attenuated the inhibitory effects on NCX of amiodarone, bepridil, and BDM, suggesting that these drugs inhibit NCX from the cytosolic side. In contrast, the trypsin-insensitive NCX inhibitors were aprindine, azimilide, dronedarone, cibenzoline, KB-R7943, SEA0400, and SN-6. KB-R7943, SEA0400, and SN-6 suppressed the uni-directional outward I NCX more potently than the uni-directional inward I NCX . The mechanism of this mode-dependency is unknown, but is suggested to be related to intracellular Na + concentration.

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“…Sodium/calcium exchange was reduced by only supratherapeutic bepridil doses (IC 50 of 30 µM) in cardiac sarcolemmal membrane vesicles and bepridil acted mode-dependently as the calcium extrusion (forward mode) was inhibited more effectively [205]. In guinea-pig ventricular cells I NCX was more sensitive to bepridil (IC 50 of 8.1 µM) [94]. HCN4 channels (underlying "funny" pacemaker current) expressed in HEK cells were also blocked by bepridil with an IC 50 of 4.9 µM whereas verapamil was much less potent inhibitor of those channels (IC 50 of 45 µM) [206].…”

Section: Bepridil (Cerm-1978)mentioning

confidence: 99%

“…Those CCAs, possessing large inhibitory actions on other ion channels, might have increased antiarrhythmic properties. The reduction of fast sodium current (I Na ) and/or Na + /Ca 2+ exchange current (I NCX ) (as with bepridil [94]) would reduce the risk of the development of triggered AP and the generation of afterdepolarizations, respectively. In rats with vitamin D3 induced calcium overload, fantofarone decreased the calcium content in the thoracic aorta, mesenteric artery and also in their heart [95].…”

Section: Potential Mechanisms Behind the Antiarrhythmic Actions Of Ccasmentioning

confidence: 99%

Class IV Antiarrhythmic Agents: New Compounds Using an Old Strategy

Szentandrássy

Nagy²,

Hegyi³

et al. 2014

CPD

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Cardiac arrhythmias are a major cause of morbidity and mortality in the industrialized world. Among their treatment regimens one can find the calcium channel antagonists (CCAs), the class IV agents. In the cardiovascular system Land T-type calcium channels are found on vascular smooth muscle cells and cardiac myocytes with well defined physiological roles. Inhibition of calcium channels by CCAs has widely been used in clinical practice for several decades. Cardiovascular disorders are one of the many fields of medicine in which CCAs are used for various reasons and conditions. The three main indications of them are hypertension, angina and various cardiac arrhythmias. The most important classes of CCAs are dihydropyridines, phenylalkylamines and benzothiazepines but some newer compounds do not fall into any of these major classes. Dihydropyridines are not used in the antiarrhythmic therapy but are good vasodilators and antianginal agents. In contrast, phenylalkylamines and benzothiazepines exert cardiac actions in vivo and therefore these are one choice of antiarrhythmic drugs. This review focuses on phenylalkylamines, benzothiazepines and on new drugs with potential antiarrhythmic action in the heart as well as the mechanisms how calcium channels antagonism can lead to an antiarrhythmic action.

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Blocking Effect of Bepridil on Na+/Ca2+ Exchange Current in Guinea Pig Cardiac Ventricular Myocytes

Cited by 36 publications

References 35 publications

Effects of Antiarrhythmic Drugs on the Hyperpolarization-Activated Cyclic Nucleotide–Gated Channel Current

Effects of Antiarrhythmic Drugs on the Hyperpolarization-Activated Cyclic Nucleotide–Gated Channel Current

Topics on the Na+/Ca2+ Exchanger: Pharmacological Characterization of Na+/Ca2+ Exchanger Inhibitors

Class IV Antiarrhythmic Agents: New Compounds Using an Old Strategy

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