Article

Pharmacological block of the slow component of the outward delayed rectifier current (I Ks) fails to lengthen rabbit ventricular muscle QT c and action potential duration

Department of Internal Medicine, Faculty of Medicine, University of Szeged, Szeged, Hungary.
British Journal of Pharmacology (Impact Factor: 4.99). 01/2001; 132(1):101-10. DOI: 10.1038/sj.bjp.0703777
Source: PubMed

ABSTRACT 1. The effects of I(Ks) block by chromanol 293B and L-735,821 on rabbit QT-interval, action potential duration (APD), and membrane current were compared to those of E-4031, a recognized I(Kr) blocker. Measurements were made in rabbit Langendorff-perfused whole hearts, isolated papillary muscle, and single isolated ventricular myocytes. 2. Neither chromanol 293B (10 microM) nor L-735,821 (100 nM) had a significant effect on QTc interval in Langendorff-perfused hearts. E-4031 (100 nM), on the other hand, significantly increased QTc interval (35.6+/-3.9%, n=8, P<0.05). 3. Similarly both chromanol 293B (10 microM) and L-735,821 (100 nM) produced little increase in papillary muscle APD (less than 7%) while pacing at cycle lengths between 300 and 5000 ms. In contrast, E-4031 (100 nM) markedly increased (30 - 60%) APD in a reverse frequency-dependent manner. 4. In ventricular myocytes, the same concentrations of chromanol 293B (10 microM), L-735,821 (100 nM) and E-4031 (1 microM) markedly or totally blocked I(Ks) and I(Kr), respectively. 5. I(Ks) tail currents activated slowly (at +30 mV, tau=888.1+/-48.2 ms, n=21) and deactivated rapidly (at -40 mV, tau=157.1+/-4.7 ms, n=22), while I(Kr) tail currents activated rapidly (at +30 mV, tau=35.5+/-3.1 ms, n=26) and deactivated slowly (at -40 mV, tau(1)=641.5+/-29.0 ms, tau(2)=6531+/-343, n=35). I(Kr) was estimated to contribute substantially more to total current density during normal ventricular muscle action potentials (i.e., after a 150 ms square pulse to +30 mV) than does I(Ks). 6. These findings indicate that block of I(Ks) is not likely to provide antiarrhythmic benefit by lengthening normal ventricular muscle QTc, APD, and refractoriness over a wide range of frequencies.

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Available from: Norbert Jost, Aug 28, 2015
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    • "Guinea pig myocytes are known to have a significantly larger I Ks current than myocytes originating from other species, including humans (Jost et al. 2004). It is known that I Ks is a relatively small current in most mammals, and it has been shown that blockade of the I Ks current does not lengthen APD in normal conditions (without sympathetic stimulation) in most species, including rabbits (Varró et al. 2000; Lengyel et al. 2001; Jost et al. 2005). Fig. 2. (A) Effect of ZS_1270B on the slow delayed rectifier K + current (I Ks ). "
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    ABSTRACT: Activators of the slow delayed rectifier K(+) current (IKs) have been suggested as promising tools for suppressing ventricular arrhythmias due to prolongation of repolarization. Recently, L-364,373 (R-L3) was nominated to activate IKs in myocytes from several species; however, in some studies, it failed to activate IKs. One later study suggested opposite modulating effects from the R-L3 enantiomers as a possible explanation for this discrepancy. Therefore, we analyzed the effect of the RL-3 enantiomers on IKs in ventricular mammalian myocytes, by applying standard microelectrode and whole-cell patch-clamp techniques at 37 °C. We synthesized 2 substances, ZS_1270B (right) and ZS_1271B (left), the 2 enantiomers of R-L3. In rabbit myocytes, ZS_1270B enhanced the IKs tail current by approximately 30%, whereas ZS_1271B reduced IKs tails by 45%. In guinea pig right ventricular preparations, ZS_1270B shortened APD90 (action potential duration measured at 90% repolarization) by 12%, whereas ZS_1271B lengthened it by approximately 15%. We concluded that R-L3 enantiomers in the same concentration range indeed have opposite modulating effects on IKs, which may explain why the racemic drug R-L3 previously failed to activate IKs. ZS_1270B is a potent IKs activator, therefore, this substance is appropriate to test whether IKs activators are ideal tools to suppress ventricular arrhythmias originating from prolongation of action potentials.
    Canadian Journal of Physiology and Pharmacology 08/2013; 91(8):586-92. DOI:10.1139/cjpp-2012-0407 · 1.55 Impact Factor
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    • "Guinea pig is known to have a significantly larger I Ks current than in myocytes originating from other species including human (Jost et al. 2004). It is known that I Ks is a relatively small current in most mammalians, and it was shown that blockade of the I Ks current did not lengthen APD in normal conditions (without sympathetic stimulation) in most species including rabbits (Varró et al. 2000; Lengyel et al. 2001; Jost et al. 2005). Fig. 2. (A) Effect of ZS_1270B on the slow delayed rectifier K + current (I Ks ). "
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    ABSTRACT: Activators of slow delayed rectifier K<sup>+</sup> current (I<sub>Ks</sub>) have been suggested as promising tools to suppress ventricular arrhythmias due to prolongation of repolarization. Recently, L-364,373 (R-L3), was nominated to activate I<sub>Ks</sub> in myocytes from several species, however, in some studies failed to activate I<sub>Ks</sub>. One later study suggested the adverse modulating effects of the R-L3 enantiomers as possible explanation for this discrepancy. Therefore, we have analysed the effect of the RL-3 enantiomers on I<sub>Ks</sub> in ventricular mammalian myocytes, by applying standard microelectrode and whole-cell patch clamp techniques at 37 C. We synthesised two substances, ZS_1270B (right) and ZS_1271B (left), the two enantiomers of R-L3. In rabbit myocytes ZS_1270B enhanced I<sub>Ks</sub> tail current by about 30%, while ZS_1271B reduced I<sub>Ks</sub> tails by 45%. In guinea pig right ventricular preparations ZS_1270B shortened APD<sub>90</sub> by 12%, while ZS_1271B, conversely lengthened it approximately 15%. We concluded that R-L3 enantiomers indeed have adverse modulating effects on I<sub>Ks</sub> in the same concentration range, which may explain why the racemic drug R-L3 previously failed to activate I<sub>Ks</sub>. ZS_1270B is a potent I<sub>Ks</sub> activator: therefore, this substance is adequate to test whether I<sub>Ks</sub> activators are indeed ideal tools to suppress ventricular arrhythmias originating from prolongation of action potentials.
    Canadian Journal of Physiology and Pharmacology 01/2013; epub. · 1.55 Impact Factor
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    • "Therefore, the slight decrease of L-type Ca2+ current by high concentration of diclofenac found in this study may also help to counteract the action potential lengthening effect of IKr blockade. The key role of IKs in ventricular repolarization was discussed in earlier works [7], [8], [31]. Full inhibition of IKs caused only a slight lengthening of repolarization in ventricular preparations, thus in normal canine ventricular muscle IKs plays a minor role in control of APD. "
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    ABSTRACT: The aim of the present work was to characterize the electrophysiological effects of the non-steroidal anti-inflammatory drug diclofenac and to study the possible proarrhythmic potency of the drug in ventricular muscle. Ion currents were recorded using voltage clamp technique in canine single ventricular cells and action potentials were obtained from canine ventricular preparations using microelectrodes. The proarrhythmic potency of the drug was investigated in an anaesthetized rabbit proarrhythmia model. Action potentials were slightly lengthened in ventricular muscle but were shortened in Purkinje fibers by diclofenac (20 µM). The maximum upstroke velocity was decreased in both preparations. Larger repolarization prolongation was observed when repolarization reserve was impaired by previous BaCl(2) application. Diclofenac (3 mg/kg) did not prolong while dofetilide (25 µg/kg) significantly lengthened the QT(c) interval in anaesthetized rabbits. The addition of diclofenac following reduction of repolarization reserve by dofetilide further prolonged QT(c). Diclofenac alone did not induce Torsades de Pointes ventricular tachycardia (TdP) while TdP incidence following dofetilide was 20%. However, the combination of diclofenac and dofetilide significantly increased TdP incidence (62%). In single ventricular cells diclofenac (30 µM) decreased the amplitude of rapid (I(Kr)) and slow (I(Ks)) delayed rectifier currents thereby attenuating repolarization reserve. L-type calcium current (I(Ca)) was slightly diminished, but the transient outward (I(to)) and inward rectifier (I(K1)) potassium currents were not influenced. Diclofenac at therapeutic concentrations and even at high dose does not prolong repolarization markedly and does not increase the risk of arrhythmia in normal heart. However, high dose diclofenac treatment may lengthen repolarization and enhance proarrhythmic risk in hearts with reduced repolarization reserve.
    PLoS ONE 12/2012; 7(12):e53255. DOI:10.1371/journal.pone.0053255 · 3.23 Impact Factor
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