Second-generation calcium antagonists: Search for greater selectivity and versatility

Singh, Bramah N.; Baky, Sherrin H.; Nademanee, Koonlawee

doi:10.1016/0002-9149(85)90634-4

Cited by 56 publications

(17 citation statements)

References 32 publications

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“…In 'fast structures', such as the atria, ventricles and the His-Purkinje system, excitation is mediated by a fast inward sodium current (see Fleckenstein, 1985). In this study, we have shown that in good agreement with their relatively selective action on slow calcium channels (Fleckenstein, 1985;Singh et al, 1985a;Sperelakis, 1987), verapamil and diltiazem at the dose levels used (0.2 mg kg-' i.v. ), only modified the rate of conduction and the refractory periods of the 'slow structures' and had no significant effects upon 'fast structures'.…”

Section: Discussionsupporting

confidence: 65%

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Electrophysiological effects of bepridil and its quaternary derivative CERM 11888 in closed chest anaesthetized dogs: a comparison with verapamil and diltiazem

Leboeuf

Lamar

Massingham

et al. 1989

British J Pharmacology

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1 The electrophysiological effects of bepridil, its quaternary derivative, CERM 11888 (methylpyrrolidinium bromide) (both 2.5mgkg-1 i.v.) and those of verapamil and diltiazem (0.2mgkg-' i.v.) were studied in closed chest anaesthetized dogs at doses used in clinical studies. 2 The four drugs caused a bradycardia with the following order of potency: bepridil > CERM 11888 > diltiazem > verapamil. 3 All the compounds slowed conduction in the AV node, increased the refractory period (RP) and decreased Wenckebach rates with the following order: verapamil > diltiazem > bepridil > CERM 11888. 4 Verapamil and diltiazem did not affect conduction or the RP in atria while bepridil weakly slowed the former and markedly increased the latter. CERM 11888 caused a lengthening of RP but this was a delayed effect. 5 In the ventricle, bepridil and CERM 11888 caused a small increase in the QRS and a more pronounced increase in the RP. Both compounds increased QTc but did not modify HV. Verapamil and diltiazem had no significant effects at the ventricular level. 6 Our results confirm that the main sites of action of calcium antagonists are the SA and AV nodes. Bepridil has a broader spectrum of activity and also acts at the atrial and ventricular levels. A comparison of the effects of bepridil with those of its quaternary derivative suggests the involvement of an intracellular action in the electrophysiological effects of bepridil.

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Section: Discussionsupporting

confidence: 65%

“…The doses of bepridil, verapamil and diltiazem are the mean doses commonly used in intravenous studies in man (Singh et al, 1985a and atrial functional refractory period (A-FRfP) (c) caused by the different compounds. Note (Figure 2a).…”

Section: Methodsmentioning

confidence: 99%

Electrophysiological effects of bepridil and its quaternary derivative CERM 11888 in closed chest anaesthetized dogs: a comparison with verapamil and diltiazem

Leboeuf

Lamar

Massingham

et al. 1989

British J Pharmacology

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show abstract

“…The class IV antiarrhythmic drugs, bepridil and prenylamine are known also to block Na4 channels i.e., exhibit class I activity (Fleckenstein, 1988;Singh et al, 1985). Verapamil has a very weak class I activity (Woosley, 1991), whilst diltiazem is devoid of class I activity.…”

Section: Electrophysiological Recordingmentioning

confidence: 99%

“…Our present results suggest that the suppression of glibenclamide-sensitivie K+ channels may underlie at least partly the mechanism of antiarrhythmic effects of calmodulin-antagonizing antiarrhythmic drugs. In this connection, it is noteworthy that bepridil, a potent calmodulin antagonist, is expected to be clinically effective for ventricular arrhythmia (Marshall et al, 1983;Singh et al, 1985).…”

Section: Effects Of Calmodulin Antagonists On Krn2391-induced K+ Currmentioning

confidence: 99%

Blockade by antiarrhythmic drugs of glibenclamide‐sensitive K⁺ channels in Xenopus oocytes

Sakuta

Okamoto

Watanabe

1992

British J Pharmacology

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“…3, 4). The effect was evaluated by comparison with pentamidine, an antiprotozoal agent, which has been known to prolong the QT interval and inhibit hERG expression (Singh et al, 1985;Cordes et al, 2005;Kuryshev et al, 2005). Incubation with pentamidine for 24 hr produced strong reduction of ma- ture, fully glycosylated hERG in the western blot experiment; nicardipine however, had no effect on hERG expression (Fig.…”

Section: Effect Of Nicardipine On Trafficking Of Herg Channelmentioning

confidence: 99%

Inhibitory Effect of Nicardipine on hERG Channel

Chung¹,

Cho²,

Cha³

et al. 2010

Biomolecules and Therapeutics

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-Drug-induced long QT syndrome is known to be associated with the onset of torsades de pointes (TdP), resulting in a fatal ventricular arrhythmia. QT interval prolongation can result from blocking the human ether-a-go-go-related gene (hERG) channel, which is important for the repolarization of cardiac action potential. Nicardipine, a Ca-channel blocker and antihypertensive agent, has been reported to increase the risk of occasional serious ventricular arrhythmias. We studied the effects of nicardipine on hERG K ＋ channels expressed in HEK293 cells and Xenopus oocytes. The cardiac electrophysiological effect of nicardipine was also investigated in this study. Our results revealed that nicardipine dose-dependently decreased the tail current of the hERG channel expressed in HEK293 cells with an IC50 of 0.43 μM. On the other hand, nicardipine did not affect hERG channel trafficking. Taken together, nicardipine inhibits the hERG channel by the mechanism of short-term channel blocking. Two S6 domain mutations, Y652A and F656A, partially attenuated (Y652A) or abolished (F656A) the hERG current blockade, suggesting that nicardipine blocks the hERG channel at the pore of the channel.

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Second-generation calcium antagonists: Search for greater selectivity and versatility

Cited by 56 publications

References 32 publications

Electrophysiological effects of bepridil and its quaternary derivative CERM 11888 in closed chest anaesthetized dogs: a comparison with verapamil and diltiazem

Electrophysiological effects of bepridil and its quaternary derivative CERM 11888 in closed chest anaesthetized dogs: a comparison with verapamil and diltiazem

Blockade by antiarrhythmic drugs of glibenclamide‐sensitive K⁺ channels in Xenopus oocytes

Inhibitory Effect of Nicardipine on hERG Channel

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Second-generation calcium antagonists: Search for greater selectivity and versatility

Cited by 56 publications

References 32 publications

Electrophysiological effects of bepridil and its quaternary derivative CERM 11888 in closed chest anaesthetized dogs: a comparison with verapamil and diltiazem

Electrophysiological effects of bepridil and its quaternary derivative CERM 11888 in closed chest anaesthetized dogs: a comparison with verapamil and diltiazem

Blockade by antiarrhythmic drugs of glibenclamide‐sensitive K+ channels in Xenopus oocytes

Inhibitory Effect of Nicardipine on hERG Channel

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Blockade by antiarrhythmic drugs of glibenclamide‐sensitive K⁺ channels in Xenopus oocytes