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Charles Antzelevitch - One of the best experts on this subject based on the ideXlab platform.
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Circulation Journal of the American Heart Association
2016Co-Authors: Torsade De Pointes, Wataru Shimizu, Er Burashnikov, Charles AntzelevitchAbstract:2 Background: The arrhythmogenic effects of hyperthermia have been highlighted in the Brugada Syndrome, but remain largely unexplored in other arrhythmic syndromes. The present study examines the effect of hyperthermia on transmural dispersion of action potential duration (TD-APD), early afterdepolarization (EAD) activity, and Torsade de Pointes (TdP) under long QT conditions. Methods and Results: Standard and floating glass microelectrodes were used to record action potentials from epicardial, M-cell, and endocardial regions of the arterially-perfused LV wedge, from tissue slices isolated from these regions, as well as from isolated Purkinje fibers. A transmural ECG was simultaneously recorded across the wedge. Under baseline conditions and in the presence of IKs block (Chromanol 293B), hyperthermia (39-400C) abbreviated APD in tissue slices from all three regions. In the presence of IKr block (E-4031), hyperthermia prolonged APD and induced or augmented EADs in M cell and Purkinje preparations at pacing cycle lengths ≥ 800 ms, but abbreviated APD in epicardium and endocardium, resulting in
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fever accentuates transmural dispersion of repolarization and facilitates development of early afterdepolarizations and torsade de pointes under long qt conditions
Circulation-arrhythmia and Electrophysiology, 2008Co-Authors: Alexander Burashnikov, Wataru Shimizu, Charles AntzelevitchAbstract:Background— The arrhythmogenic effects of hyperthermia have been highlighted in the Brugada syndrome but remain largely unexplored in other arrhythmic syndromes. The present study examines the effect of hyperthermia on transmural dispersion of action potential duration (TD-APD), early afterdepolarization (EAD) activity, and torsade de pointes (TdP) under long-QT conditions. Methods and Results— Standard and floating glass microelectrodes were used to record action potentials from epicardial, M cell, and endocardial regions of the arterially perfused left ventricle wedge, from tissue slices isolated from these regions, and from isolated Purkinje fibers. A transmural ECG was simultaneously recorded across the wedge. Under baseline conditions and in the presence of IKs block (Chromanol 293B), hyperthermia (39°C to 40°C) abbreviated APD in tissue slices from all 3 regions. In the presence of IKr block (E-4031), hyperthermia prolonged APD and induced or augmented EADs in M cell and Purkinje preparations at pacing cycle lengths ≥800 ms but abbreviated APD in epicardium and endocardium, resulting in a marked accentuation of TD-APD. Ryanodine prevented the hyperthermia-induced EAD. In perfused wedge preparations, hyperthermia abbreviated APD throughout both in the absence or presence of IKr or IKs block and did not induce EADs or TdP. Combined IKr and IKs block increased TD-APD and induced EADs (4/12) and spontaneous TdP (3/12) at 36°C to 37°C; hyperthermia (39°C to 40°C) further accentuated TD-APD and facilitated the development of EAD activity (9/12) and TdP (6/12). Conclusions— Our findings suggest that hyperthermia can be associated with an increased arrhythmic risk when the repolarization reserve of the myocardium is compromised. Received January 22, 2007; accepted May 30, 2008.
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HMR 1556, a potent and selective blocker of slowly activating delayed rectifier potassium current.
Journal of cardiovascular pharmacology, 2003Co-Authors: George Thomas, Uwe Gerlach, Charles AntzelevitchAbstract:The slowly activating delayed rectifier potassium current (I Ks ) contributes prominently to ventricular repolarization of the cardiac action potential. Development of a selective I Ks blocker is important for the elucidation of the physiologic and pathophysiologic relevance of I Ks and the development of antiarrhythmic strategies. HMR 1556 [(3R,4S)-(+)-N-[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy) chroman-4-yl]-N-methyl-methanesulfonamide] is a new Chromanol derivative developed as a selective I Ks blocker. Chromanol 293B, the most specific I Ks blocker currently available, also inhibits the transient outward current (I to ). HMR 1556 was examined for its effects on I Ks compared with rapidly activating delayed rectifier (I Kr ), inward rectifier (I Kl ), I to , and L-type calcium (I Ca,L ) currents in canine left ventricular myocytes. HMR 1556 (0.5- 500 nM) inhibited I Ks in a concentration-dependent manner (IC 50 of 10.5 nM, compared with Chromanol 293B's IC 50 of 1.8 μM). Inhibition of I to was observed only at relatively high concentrations (IC 50 of 33.9 μM, comparable to Chromanol 293B's IC 50 of 38 μM). High concentrations of HMR 1556 also inhibited I Ca,L (IC 50 of 27.5 μM) and I Kr (IC 50 of 12.6 μM) while I K1 was unaffected. Our results indicate that HMR 1556 is superior to Chromanol 293B in its potency and specificity for inhibition of I Ks , making it a valuable experimental tool and a potential therapeutic agent.
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prominent iks in epicardium and endocardium contributes to development of transmural dispersion of repolarization but protects against development of early afterdepolarizations
Journal of Cardiovascular Electrophysiology, 2002Co-Authors: Alexander Burashnikov, Charles AntzelevitchAbstract:IKs Prevents EADs in Epicardium and Endocardium.Introduction: Previous studies from our laboratory demonstrated (1) a much larger IKs and (2) inability to induce early afterdepolarization (EAD) activity in epicardial and endocardial cells versus M cells. This study tests the hypothesis that these two characteristics are interrelated. Methods and Results: Standard and floating microelectrode techniques were used to record transmembrane activity from the canine left ventricular epicardial, M, and endocardial regions in isolated tissue slices and arterially perfused wedge preparations. The IKr blocker E-4031 (1 to 10 μM) caused prominent prolongation of action potential duration (APD) and induced EADs in tissues isolated from the M region, but not those from epicardium or endocardium, causing a large transmural dispersion of APD. In contrast, the IKs blocker Chromanol 293B (10 to 30 μM) produced moderate prolongation of APD without EADs in all three tissue types. The combination of E–4031 (1 μM) and Chromanol 293B (30 μM) resulted in profound prolongation of APD and the development of EADs in all three tissue types. In the perfused wedge, neither E–4031 nor Chromanol 293B alone could induce EADs. In combination, the two drugs caused significant prolongation of APD and EADs in all three transmural regions. Conclusion: Our results support the hypothesis that a prominent IKs is responsible for the ability of epicardium and endocardium to resist some but not all of the arrhythmogenic effects of IKr block. The data highlight the critical importance of IKs in the canine heart and the significant role of electrotonic interactions in minimizing the development of an arrhythmogenic substrate when repolarization reserve is reduced.
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effects of a k channel opener to reduce transmural dispersion of repolarization and prevent torsade de pointes in lqt1 lqt2 and lqt3 models of the long qt syndrome
Circulation, 2000Co-Authors: Wataru Shimizu, Charles AntzelevitchAbstract:BACKGROUND: This study examines the effects of nicorandil, a K(+) channel opener, on transmural dispersion of repolarization (TDR) and induction of torsade de pointes (TdP) under conditions mimicking the LQT1, LQT2, and LQT3 forms of the congenital long-QT syndrome (LQTS). METHODS AND RESULTS: Transmembrane action potentials of epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle together with a transmural ECG. Chromanol 293B (30 micromol/L) was used to block I(Ks) (LQT1 model). Isoproterenol (50 to 100 nmol/L) was used to mimic an increase in beta-adrenergic tone, d-sotalol (100 micromol/L) to block I(Kr) (LQT2 model), and ATX-II (20 nmol/L) to augment late I(Na) (LQT3 model). Isoproterenol+Chromanol 293B, d-sotalol, and ATX-II produced preferential prolongation of the action potential duration at 90% repolarization (APD(90)) of the M cell, an increase of TDR, and spontaneous as well as stimulation-induced TdP (LQT1, 3/6; LQT2, 3/6; LQT3, 5/6). Nicorandil (2 to 20 micromol/L) abbreviated the QT interval and APD(90) of the 3 cell types in the 3 models. High concentrations (10 to 20 micromol/L) completely reversed the effects of 293B+/-isoproterenol and those of d-sotalol to increase APD(90) and TDR and to induce TdP in LQT1 and LQT2 models. Nicorandil 20 micromol/L reversed only 50% of the effect of ATX-II and failed to completely suppress TdP in the LQT3 model (5/6 to 3/6). CONCLUSIONS: Our data suggest that K(+) channel openers may be capable of abbreviating the long QT interval, reducing TDR, and preventing spontaneous and stimulation-induced TdP when congenital or acquired LQTS is secondary to reduced I(Kr) or I(Ks) but less so when it is due to augmented late I(Na).
Hiroshi Matsuura - One of the best experts on this subject based on the ideXlab platform.
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cellular and ionic mechanism for drug induced long qt syndrome and effectiveness of verapamil
Journal of the American College of Cardiology, 2005Co-Authors: Takeshi Aiba, Wataru Shimizu, Weiguang Ding, Futoshi Toyoda, Hiroshi Matsuura, Masashi Inagaki, Takashi Noda, Shunichiro Miyoshi, Dimitar P Zankov, Minoru HorieAbstract:Objectives We examined the cellular and ionic mechanism for QT prolongation and subsequent Torsade de Pointes (TdP) and the effect of verapamil under conditions mimicking KCNQ1(IKsgene) defect linked to acquired long QT syndrome (LQTS). Background Agents with an IKr-blocking effect often induce marked QT prolongation in patients with acquired LQTS. Previous reports demonstrated a relationship between subclinical mutations in cardiac K+channel genes and a risk of drug-induced TdP. Methods Transmembrane action potentials from epicardial (EPI), midmyocardial (M), and endocardial (ENDO) cells were simultaneously recorded, together with a transmural electrocardiogram, at a basic cycle length of 2,000 ms in arterially perfused feline left ventricular preparations. Results The IKrblock (E-4031: 1 μmol/l) under control conditions (n = 5) prolonged the QT interval but neither increased transmural dispersion of repolarization (TDR) nor induced arrhythmias. However, the IKrblocker under conditions with IKssuppression by Chromanol 293B 10 μmol/l mimicking the KCNQ1defect (n = 10) preferentially prolonged action potential duration (APD) in EPI rather than M or ENDO, thereby dramatically increasing the QT interval and TDR. Spontaneous or epinephrine-induced early afterdepolarizations (EADs) were observed in EPI, and subsequent TdP occurred only under both IKsand IKrsuppression. Verapamil (0.1 to 5.0 μmol/l) dose-dependently abbreviated APD in EPI more than in M and ENDO, thereby significantly decreasing the QT interval, TDR, and suppressing EADs and TdP. Conclusions Subclinical IKsdysfunction could be a risk of drug-induced TdP. Verapamil is effective in decreasing the QT interval and TDR and in suppressing EADs, thus preventing TdP in the model of acquired LQTS.
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blocking action of Chromanol 293B on the slow component of delayed rectifier k current in guinea pig sino atrial node cells
British Journal of Pharmacology, 2002Co-Authors: Weiguang Ding, Futoshi Toyoda, Hiroshi MatsuuraAbstract:In guinea-pig sino-atrial (SA) node cells the delayed rectifier K+ current (IK) is composed of rapidly and slowly activating components of IK (IKr and IKs, respectively). The present study was undertaken to characterize the blocking action of the Chromanol derivative 293B on IKs in guinea-pig SA node cells using whole-cell patch-clamp technique. Bath application of 293B blocked IKs, elicited by 4-s depolarizing voltage pulses from a holding potential of −50 mV, under conditions in which the L-type Ca2+ current (ICa,L) and IKr were inhibited; the effect was concentration-dependent with an IC50 of 5.3 μM, when evaluated by the decrease in the amplitude of IKs tail current following 4-s depolarizing voltage steps to +50 mV. The 293B block of IKs progressed with time during depolarizing voltage steps with a more rapid block at higher concentrations. The block of IKs by 293B was fully reversed within a few minutes after washing off the drug, even when a maximal effect (a nearly full block) was achieved at high drug concentration (50 μM). Bath application of 293B at 50 μM greatly and reversibly reduced the amplitude of IKs which is maximally stimulated by β-adrenergic agonist isoprenaline (1 μM), while the degree of 293B block of the isoprenaline-stimulated IKs was slightly but significantly smaller than that of non-stimulated IKs (94.0±0.98% block, n=6 vs 99.4±0.45% block, n=6; P<0.01). We conclude that, in guinea-pig SA node cells (i) 293B is a potent and fully reversible blocker of IKs in control and during β-adrenergic stimulation and (ii) block with 293B occurs in a time-dependent manner during depolarizing voltage steps. Keywords: Delayed rectifier K+ current, IKs, Chromanol 293B, isoprenaline, sino-atrial node, time-dependent block Introduction The delayed rectifier K+ current (IK) is gradually activated during the plateau phase of action potentials and provides an outward current which facilitates phase 3 repolarization in various cardiac cell types, including sino-atrial (SA) node, atrial and ventricular cells. In addition, a deactivation of IK during membrane repolarization in pacemaker SA node cells is considered to be involved in the onset of a net inward current at the maximum diastolic potential (MDP) that precedes the slow diastolic depolarization (for a review see Irisawa et al., 1993). It has been demonstrated in many cardiac cells that IK can be separated into two distinct components on the basis of the differential sensitivity to block by methanesulphonanilide class III antiarrhythmic drugs such as E-4031, d-sotalol and dofetilide (Sanguinetti & Jurkiewicz, 1990; 1991; Carmeliet, 1992; Jurkiewicz & Sanguinetti, 1993; Wang et al., 1994; Liu & Antzelevitch, 1995; Li et al., 1996; Gintant, 1996); the drug-sensitive current activates rapidly and exhibits a marked inward rectification (designated as IKr) whereas the drug-resistant current displays slower activation kinetics and a minimal rectification (designated as IKs). Subsequent molecular biological studies have identified the distinct proteins underlying IKr and IKs channels: the potassium channel protein KVLQT1 associates with minK (IsK) protein to produce IKs channels (Barhanin et al., 1996; Sanguinetti et al., 1996), while human ether-a-go-go related gene (HERG) protein forms the pore-forming subunit of IKr channels (Curran et al., 1995; Sanguinetti et al., 1995; Trudeau et al., 1995). The Chromanol derivative 293B was found to be a potent blocker not only for IKs in guinea-pig ventricular cells but also for the membrane current through the IsK proteins heterologously expressed in Xenopus oocytes (Busch et al., 1996; Suessbrich et al., 1996). Subsequent studies have confirmed the highly selective blocking action of 293B on IKs in many types of isolated cardiac cells (Bosch et al., 1998; Fujisawa et al., 2000; Ono et al., 2000; Lei et al., 2002). As for molecular basis for 293B action on IKs channels, it has been suggested that KvLQT1 protein represents a relevant target for the actions of 293B (Loussouarn et al., 1997) while minK protein also acts allosterically to facilitate 293B binding to KvLQT1 protein (Busch et al., 1997; Lerche et al., 2000). In the present study we characterized the blocking action of 293B on IKs under control conditions and during exposure to β-adrenergic agonist isoprenaline in isolated guinea-pig SA node cells using the whole-cell patch-clamp technique. The results demonstrate that 293B is a potent and fully reversible blocker of IKs in the absence and presence of isoprenaline and that 293B preferentially affects IKs channels in an open state.
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Blocking action of Chromanol 293B on the slow component of delayed rectifier K(+) current in guinea-pig sino-atrial node cells.
British journal of pharmacology, 2002Co-Authors: Weiguang Ding, Futoshi Toyoda, Hiroshi MatsuuraAbstract:In guinea-pig sino-atrial (SA) node cells the delayed rectifier K+ current (IK) is composed of rapidly and slowly activating components of IK (IKr and IKs, respectively). The present study was undertaken to characterize the blocking action of the Chromanol derivative 293B on IKs in guinea-pig SA node cells using whole-cell patch-clamp technique. Bath application of 293B blocked IKs, elicited by 4-s depolarizing voltage pulses from a holding potential of −50 mV, under conditions in which the L-type Ca2+ current (ICa,L) and IKr were inhibited; the effect was concentration-dependent with an IC50 of 5.3 μM, when evaluated by the decrease in the amplitude of IKs tail current following 4-s depolarizing voltage steps to +50 mV. The 293B block of IKs progressed with time during depolarizing voltage steps with a more rapid block at higher concentrations. The block of IKs by 293B was fully reversed within a few minutes after washing off the drug, even when a maximal effect (a nearly full block) was achieved at high drug concentration (50 μM). Bath application of 293B at 50 μM greatly and reversibly reduced the amplitude of IKs which is maximally stimulated by β-adrenergic agonist isoprenaline (1 μM), while the degree of 293B block of the isoprenaline-stimulated IKs was slightly but significantly smaller than that of non-stimulated IKs (94.0±0.98% block, n=6 vs 99.4±0.45% block, n=6; P
Wataru Shimizu - One of the best experts on this subject based on the ideXlab platform.
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Circulation Journal of the American Heart Association
2016Co-Authors: Torsade De Pointes, Wataru Shimizu, Er Burashnikov, Charles AntzelevitchAbstract:2 Background: The arrhythmogenic effects of hyperthermia have been highlighted in the Brugada Syndrome, but remain largely unexplored in other arrhythmic syndromes. The present study examines the effect of hyperthermia on transmural dispersion of action potential duration (TD-APD), early afterdepolarization (EAD) activity, and Torsade de Pointes (TdP) under long QT conditions. Methods and Results: Standard and floating glass microelectrodes were used to record action potentials from epicardial, M-cell, and endocardial regions of the arterially-perfused LV wedge, from tissue slices isolated from these regions, as well as from isolated Purkinje fibers. A transmural ECG was simultaneously recorded across the wedge. Under baseline conditions and in the presence of IKs block (Chromanol 293B), hyperthermia (39-400C) abbreviated APD in tissue slices from all three regions. In the presence of IKr block (E-4031), hyperthermia prolonged APD and induced or augmented EADs in M cell and Purkinje preparations at pacing cycle lengths ≥ 800 ms, but abbreviated APD in epicardium and endocardium, resulting in
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fever accentuates transmural dispersion of repolarization and facilitates development of early afterdepolarizations and torsade de pointes under long qt conditions
Circulation-arrhythmia and Electrophysiology, 2008Co-Authors: Alexander Burashnikov, Wataru Shimizu, Charles AntzelevitchAbstract:Background— The arrhythmogenic effects of hyperthermia have been highlighted in the Brugada syndrome but remain largely unexplored in other arrhythmic syndromes. The present study examines the effect of hyperthermia on transmural dispersion of action potential duration (TD-APD), early afterdepolarization (EAD) activity, and torsade de pointes (TdP) under long-QT conditions. Methods and Results— Standard and floating glass microelectrodes were used to record action potentials from epicardial, M cell, and endocardial regions of the arterially perfused left ventricle wedge, from tissue slices isolated from these regions, and from isolated Purkinje fibers. A transmural ECG was simultaneously recorded across the wedge. Under baseline conditions and in the presence of IKs block (Chromanol 293B), hyperthermia (39°C to 40°C) abbreviated APD in tissue slices from all 3 regions. In the presence of IKr block (E-4031), hyperthermia prolonged APD and induced or augmented EADs in M cell and Purkinje preparations at pacing cycle lengths ≥800 ms but abbreviated APD in epicardium and endocardium, resulting in a marked accentuation of TD-APD. Ryanodine prevented the hyperthermia-induced EAD. In perfused wedge preparations, hyperthermia abbreviated APD throughout both in the absence or presence of IKr or IKs block and did not induce EADs or TdP. Combined IKr and IKs block increased TD-APD and induced EADs (4/12) and spontaneous TdP (3/12) at 36°C to 37°C; hyperthermia (39°C to 40°C) further accentuated TD-APD and facilitated the development of EAD activity (9/12) and TdP (6/12). Conclusions— Our findings suggest that hyperthermia can be associated with an increased arrhythmic risk when the repolarization reserve of the myocardium is compromised. Received January 22, 2007; accepted May 30, 2008.
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cellular and ionic mechanism for drug induced long qt syndrome and effectiveness of verapamil
Journal of the American College of Cardiology, 2005Co-Authors: Takeshi Aiba, Wataru Shimizu, Weiguang Ding, Futoshi Toyoda, Hiroshi Matsuura, Masashi Inagaki, Takashi Noda, Shunichiro Miyoshi, Dimitar P Zankov, Minoru HorieAbstract:Objectives We examined the cellular and ionic mechanism for QT prolongation and subsequent Torsade de Pointes (TdP) and the effect of verapamil under conditions mimicking KCNQ1(IKsgene) defect linked to acquired long QT syndrome (LQTS). Background Agents with an IKr-blocking effect often induce marked QT prolongation in patients with acquired LQTS. Previous reports demonstrated a relationship between subclinical mutations in cardiac K+channel genes and a risk of drug-induced TdP. Methods Transmembrane action potentials from epicardial (EPI), midmyocardial (M), and endocardial (ENDO) cells were simultaneously recorded, together with a transmural electrocardiogram, at a basic cycle length of 2,000 ms in arterially perfused feline left ventricular preparations. Results The IKrblock (E-4031: 1 μmol/l) under control conditions (n = 5) prolonged the QT interval but neither increased transmural dispersion of repolarization (TDR) nor induced arrhythmias. However, the IKrblocker under conditions with IKssuppression by Chromanol 293B 10 μmol/l mimicking the KCNQ1defect (n = 10) preferentially prolonged action potential duration (APD) in EPI rather than M or ENDO, thereby dramatically increasing the QT interval and TDR. Spontaneous or epinephrine-induced early afterdepolarizations (EADs) were observed in EPI, and subsequent TdP occurred only under both IKsand IKrsuppression. Verapamil (0.1 to 5.0 μmol/l) dose-dependently abbreviated APD in EPI more than in M and ENDO, thereby significantly decreasing the QT interval, TDR, and suppressing EADs and TdP. Conclusions Subclinical IKsdysfunction could be a risk of drug-induced TdP. Verapamil is effective in decreasing the QT interval and TDR and in suppressing EADs, thus preventing TdP in the model of acquired LQTS.
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effects of a k channel opener to reduce transmural dispersion of repolarization and prevent torsade de pointes in lqt1 lqt2 and lqt3 models of the long qt syndrome
Circulation, 2000Co-Authors: Wataru Shimizu, Charles AntzelevitchAbstract:BACKGROUND: This study examines the effects of nicorandil, a K(+) channel opener, on transmural dispersion of repolarization (TDR) and induction of torsade de pointes (TdP) under conditions mimicking the LQT1, LQT2, and LQT3 forms of the congenital long-QT syndrome (LQTS). METHODS AND RESULTS: Transmembrane action potentials of epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle together with a transmural ECG. Chromanol 293B (30 micromol/L) was used to block I(Ks) (LQT1 model). Isoproterenol (50 to 100 nmol/L) was used to mimic an increase in beta-adrenergic tone, d-sotalol (100 micromol/L) to block I(Kr) (LQT2 model), and ATX-II (20 nmol/L) to augment late I(Na) (LQT3 model). Isoproterenol+Chromanol 293B, d-sotalol, and ATX-II produced preferential prolongation of the action potential duration at 90% repolarization (APD(90)) of the M cell, an increase of TDR, and spontaneous as well as stimulation-induced TdP (LQT1, 3/6; LQT2, 3/6; LQT3, 5/6). Nicorandil (2 to 20 micromol/L) abbreviated the QT interval and APD(90) of the 3 cell types in the 3 models. High concentrations (10 to 20 micromol/L) completely reversed the effects of 293B+/-isoproterenol and those of d-sotalol to increase APD(90) and TDR and to induce TdP in LQT1 and LQT2 models. Nicorandil 20 micromol/L reversed only 50% of the effect of ATX-II and failed to completely suppress TdP in the LQT3 model (5/6 to 3/6). CONCLUSIONS: Our data suggest that K(+) channel openers may be capable of abbreviating the long QT interval, reducing TDR, and preventing spontaneous and stimulation-induced TdP when congenital or acquired LQTS is secondary to reduced I(Kr) or I(Ks) but less so when it is due to augmented late I(Na).
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effects of a k channel opener to reduce transmural dispersion of repolarization and prevent torsade de pointes in lqt1 lqt2 and lqt3 models of the long qt syndrome
Circulation, 2000Co-Authors: Wataru Shimizu, Charles AntzelevitchAbstract:Background—This study examines the effects of nicorandil, a K+ channel opener, on transmural dispersion of repolarization (TDR) and induction of torsade de pointes (TdP) under conditions mimicking the LQT1, LQT2, and LQT3 forms of the congenital long-QT syndrome (LQTS). Methods and Results—Transmembrane action potentials of epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle together with a transmural ECG. Chromanol 293B (30 μmol/L) was used to block IKs (LQT1 model). Isoproterenol (50 to 100 nmol/L) was used to mimic an increase in β-adrenergic tone, d-sotalol (100 μmol/L) to block IKr (LQT2 model), and ATX-II (20 nmol/L) to augment late INa (LQT3 model). Isoproterenol+Chromanol 293B, d-sotalol, and ATX-II produced preferential prolongation of the action potential duration at 90% repolarization (APD90) of the M cell, an increase of TDR, and spontaneous as well as stimulation-induced TdP (LQT1, 3/6; LQT2, 3/6; LQT3, 5/6). Nicorandil ...
Julius Gyula Papp - One of the best experts on this subject based on the ideXlab platform.
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Interaction of different potassium channels in cardiac repolarization in dog ventricular preparations: role of repolarization reserve.
British Journal of Pharmacology, 2002Co-Authors: Peter Biliczki, Norbert Iost, Laszlo Virag, Julius Gyula Papp, Andras VarroAbstract:The aim of this study was to investigate the possible role of the interaction of different potassium channels in dog ventricular muscle, by applying the conventional microelectrode and whole cell patch-clamp techniques at 37°C. Complete block of IKr by 1 μM dofetilide lengthened action potential duration (APD) by 45.6±3.6% at 0.2 Hz (n=13). Chromanol 293B applied alone at 10 μM (a concentration which selectively blocks IKs) did not markedly lengthen APD (
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interaction of different potassium channels in cardiac repolarization in dog ventricular preparations role of repolarization reserve
British Journal of Pharmacology, 2002Co-Authors: Peter Biliczki, Norbert Iost, Laszlo Virag, Julius Gyula Papp, Andras VarroAbstract:1 The aim of this study was to investigate the possible role of the interaction of different potassium channels in dog ventricular muscle, by applying the conventional microelectrode and whole cell patch-clamp techniques at 37 degrees C. 2 Complete block of I(Kr) by 1 micro M dofetilide lengthened action potential duration (APD) by 45.6+/-3.6% at 0.2 Hz (n=13). Chromanol 293B applied alone at 10 micro M (a concentration which selectively blocks I(Ks)) did not markedly lengthen APD (<7%), but when repolarization had already been prolonged by complete I(Kr) block with 1 micro M dofetilide, inhibition of I(Ks) with 10 micro M Chromanol 293B substantially delayed repolarization by 38.5+/-8.2% at 0.2 Hz (n=6). 3 BaCl(2), at a concentration of 10 micro M which blocks I(Kl) without affecting other currents, lengthened APD by 33.0+/-3.1% (n=11), but when I(Kr) was blocked with 1 micro M dofetilide, 10 micro M BaCl(2) produced a more excessive rate dependent lengthening in APD, frequently (in three out of seven preparations) initiating early afterdepolarizations. 4 These findings indicate that if only one type of potassium channels is inhibited in dog ventricular muscle, excessive APD lengthening is not likely to occur. Dog ventricular myocytes seem to repolarize with a strong safety margin ('repolarization reserve'). However, when this normal 'repolarization reserve' is attenuated, otherwise minimal or moderate potassium current inhibition can result in excessive and potentially proarrhythmic prolongation of the ventricular APD. Therefore, application of drugs which are able to block more than one type of potassium channel is probably more hazardous than the use of a specific inhibitor of one given sort of potassium channel, and when simultaneous blockade of several kinds of potassium channel may be presumed, a detailed study is needed to define the determinants of 'repolarization reserve'.
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pharmacological block of the slow component of the outward delayed rectifier current iks fails to lengthen rabbit ventricular muscle qtc and action potential duration
British Journal of Pharmacology, 2001Co-Authors: Csaba Lengyel, Norbert Iost, Laszlo Virag, Andras Varro, David A Lathrop, Julius Gyula PappAbstract: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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pharmacological block of the slow component of the outward delayed rectifier current iks fails to lengthen rabbit ventricular muscle qtc and action potential duration
British Journal of Pharmacology, 2001Co-Authors: Csaba Lengyel, Norbert Iost, Laszlo Virag, Andras Varro, David A Lathrop, Julius Gyula PappAbstract:The effects of IKs 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 IKr blocker. Measurements were made in rabbit Langendorff-perfused whole hearts, isolated papillary muscle, and single isolated ventricular myocytes. Neither Chromanol 293B (10 μM) 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). Similarly both Chromanol 293B (10 μM) 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. In ventricular myocytes, the same concentrations of Chromanol 293B (10 μM), L-735,821 (100 nM) and E-4031 (1 μM) markedly or totally blocked IKs and IKr, respectively. IKs tail currents activated slowly (at +30 mV, τ=888.1±48.2 ms, n=21) and deactivated rapidly (at −40 mV, τ=157.1±4.7 ms, n=22), while IKr tail currents activated rapidly (at +30 mV, τ=35.5±3.1 ms, n=26) and deactivated slowly (at −40 mV, τ1=641.5±29.0 ms, τ2=6531±343, n=35). IKr 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 IKs. These findings indicate that block of IKs is not likely to provide antiarrhythmic benefit by lengthening normal ventricular muscle QTc, APD, and refractoriness over a wide range of frequencies. Keywords: IKs, action potential duration; rabbit heart; L-735,821; Chromanol 293B; arrhythmia Introduction Pharmacological lengthening of cardiac action potential duration (APD) is a well-recognized means of cardiac arrhythmia suppression (Singh & Vaughan Williams, 1970 ; Singh, 1988). Pharmacologic agents that target the membrane current recognized as most responsible for initiation of final action potential repolarization have therefore been intensely sought and developed over the past two decades as new antiarrhythmic agents. This current, the outwardly directed delayed rectifier potassium current (IK) in most species (Noble & Tsien, 1969; Sanguinetti & Jurkiewicz, 1990; Follmer & Colatsky, 1990; Varro et al., 1993; Gintant, 1996; Salata et al., 1996b) including man (Li et al., 1996; Iost et al., 1998; 1999) consists of both a rapid (IKr) and slow (IKs) component. The two components of IK differ from each other in terms of their drug sensitivity, current rectification, and kinetics (Sanguinetti & Jurkiewicz, 1990; Liu & Antzelevitch, 1995; Carmeliet, 1992; 1993; Gintant, 1996; Heath & Terrar, 1996b). Specific IKr blockers (e.g., d-sotalol, E-4031, and more recently dofetilide) greatly lengthen cardiac APD (Singh & Vaughan Williams, 1970; Strauss et al., 1970; Lathrop, 1985; Jurkiewicz & Sanguinetti, 1993) and several are well recognized as useful in ablating cardiac arrhythmias in man (Singh, 1988; Hohnloser & Woosley, 1994). All IKr blockers display ‘reverse use-dependency' (Hondeghem & Snyders, 1990) characterized by greater increases in APD at long diastolic intervals than at short ones. Thus, when the time between initiation of successive action potentials is short and an APD increase is expected to provide the most antiarrhythmic benefit, the actual APD increase is least. Conversely, when the time between successive action potentials is long, IKr block produces a far greater increase in APD. Long APDs due to block of IKr at long diastolic intervals and slow heart rates are associated with induction of early after depolarizations believed to trigger Torsade de Pointes ventricular arrhythmias (Hohnloser & Woosley, 1994). Selective IKs block, on the other hand, is hypothesized to increase APD and refractoriness in a frequency-independent manner (Jurkiewicz & Sanguinetti, 1993). Because of this, the search for selective IKs blockers has intensified as they may represent novel antiarrhythmic agents devoid of the risk of Torsade de Pointes arrhythmia induction. Propofol, thiopenthone (Heath & Terrar, 1996a) and indapamide (Turgeon et al., 1994) were first recognized as IKs blockers in guinea-pig ventricular myocytes. However, both these agents require concentrations greater than 100 μM to produce IKs block so that concerns over their selectivity and possible therapeutic usefulness have been justifiably raised. Three newer compounds, Chromanol 293B (Busch et al., 1996; Varro et al., 2000), L-735,821 (Salata et al., 1996a; Cordeiro et al., 1998; Varro et al., 2000) and L-768,673 (Selnick et al., 1997; Lynch et al., 1999) have recently been reported to selectively block IKs. The effects of these compounds on QTc and cardiac action potential configuration, however, have not been characterized in rabbit, which represents a species widely used to determine the effects of new antiarrhythmic agents intended for use in man. Available published results of describing Chromanol 293B and L-735821 effects, in fact, have often contradicted each other (e.g., Schreieck et al., 1997; Cordeiro et al., 1998; Anyukhovsky et al., 1999; Varro et al., 2000). These contradictory findings have caused us to question whether these differences may be due to species and regional variations in IKs (Varro et al., 2000). Therefore, the major objective of this study was to characterize the effects of Chromanol 293B and L-735,821 on whole heart QTc, papillary muscle APD, and isolated myocyte membrane current in rabbit; a species widely used for antiarrhythmic drug testing. For comparison, we compared the effects of the two IKs blockers to those of E-4031, a recognized IKr blocker.
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cellular and ionic mechanism for drug induced long qt syndrome and effectiveness of verapamil
Journal of the American College of Cardiology, 2005Co-Authors: Takeshi Aiba, Wataru Shimizu, Weiguang Ding, Futoshi Toyoda, Hiroshi Matsuura, Masashi Inagaki, Takashi Noda, Shunichiro Miyoshi, Dimitar P Zankov, Minoru HorieAbstract:Objectives We examined the cellular and ionic mechanism for QT prolongation and subsequent Torsade de Pointes (TdP) and the effect of verapamil under conditions mimicking KCNQ1(IKsgene) defect linked to acquired long QT syndrome (LQTS). Background Agents with an IKr-blocking effect often induce marked QT prolongation in patients with acquired LQTS. Previous reports demonstrated a relationship between subclinical mutations in cardiac K+channel genes and a risk of drug-induced TdP. Methods Transmembrane action potentials from epicardial (EPI), midmyocardial (M), and endocardial (ENDO) cells were simultaneously recorded, together with a transmural electrocardiogram, at a basic cycle length of 2,000 ms in arterially perfused feline left ventricular preparations. Results The IKrblock (E-4031: 1 μmol/l) under control conditions (n = 5) prolonged the QT interval but neither increased transmural dispersion of repolarization (TDR) nor induced arrhythmias. However, the IKrblocker under conditions with IKssuppression by Chromanol 293B 10 μmol/l mimicking the KCNQ1defect (n = 10) preferentially prolonged action potential duration (APD) in EPI rather than M or ENDO, thereby dramatically increasing the QT interval and TDR. Spontaneous or epinephrine-induced early afterdepolarizations (EADs) were observed in EPI, and subsequent TdP occurred only under both IKsand IKrsuppression. Verapamil (0.1 to 5.0 μmol/l) dose-dependently abbreviated APD in EPI more than in M and ENDO, thereby significantly decreasing the QT interval, TDR, and suppressing EADs and TdP. Conclusions Subclinical IKsdysfunction could be a risk of drug-induced TdP. Verapamil is effective in decreasing the QT interval and TDR and in suppressing EADs, thus preventing TdP in the model of acquired LQTS.
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blocking action of Chromanol 293B on the slow component of delayed rectifier k current in guinea pig sino atrial node cells
British Journal of Pharmacology, 2002Co-Authors: Weiguang Ding, Futoshi Toyoda, Hiroshi MatsuuraAbstract:In guinea-pig sino-atrial (SA) node cells the delayed rectifier K+ current (IK) is composed of rapidly and slowly activating components of IK (IKr and IKs, respectively). The present study was undertaken to characterize the blocking action of the Chromanol derivative 293B on IKs in guinea-pig SA node cells using whole-cell patch-clamp technique. Bath application of 293B blocked IKs, elicited by 4-s depolarizing voltage pulses from a holding potential of −50 mV, under conditions in which the L-type Ca2+ current (ICa,L) and IKr were inhibited; the effect was concentration-dependent with an IC50 of 5.3 μM, when evaluated by the decrease in the amplitude of IKs tail current following 4-s depolarizing voltage steps to +50 mV. The 293B block of IKs progressed with time during depolarizing voltage steps with a more rapid block at higher concentrations. The block of IKs by 293B was fully reversed within a few minutes after washing off the drug, even when a maximal effect (a nearly full block) was achieved at high drug concentration (50 μM). Bath application of 293B at 50 μM greatly and reversibly reduced the amplitude of IKs which is maximally stimulated by β-adrenergic agonist isoprenaline (1 μM), while the degree of 293B block of the isoprenaline-stimulated IKs was slightly but significantly smaller than that of non-stimulated IKs (94.0±0.98% block, n=6 vs 99.4±0.45% block, n=6; P<0.01). We conclude that, in guinea-pig SA node cells (i) 293B is a potent and fully reversible blocker of IKs in control and during β-adrenergic stimulation and (ii) block with 293B occurs in a time-dependent manner during depolarizing voltage steps. Keywords: Delayed rectifier K+ current, IKs, Chromanol 293B, isoprenaline, sino-atrial node, time-dependent block Introduction The delayed rectifier K+ current (IK) is gradually activated during the plateau phase of action potentials and provides an outward current which facilitates phase 3 repolarization in various cardiac cell types, including sino-atrial (SA) node, atrial and ventricular cells. In addition, a deactivation of IK during membrane repolarization in pacemaker SA node cells is considered to be involved in the onset of a net inward current at the maximum diastolic potential (MDP) that precedes the slow diastolic depolarization (for a review see Irisawa et al., 1993). It has been demonstrated in many cardiac cells that IK can be separated into two distinct components on the basis of the differential sensitivity to block by methanesulphonanilide class III antiarrhythmic drugs such as E-4031, d-sotalol and dofetilide (Sanguinetti & Jurkiewicz, 1990; 1991; Carmeliet, 1992; Jurkiewicz & Sanguinetti, 1993; Wang et al., 1994; Liu & Antzelevitch, 1995; Li et al., 1996; Gintant, 1996); the drug-sensitive current activates rapidly and exhibits a marked inward rectification (designated as IKr) whereas the drug-resistant current displays slower activation kinetics and a minimal rectification (designated as IKs). Subsequent molecular biological studies have identified the distinct proteins underlying IKr and IKs channels: the potassium channel protein KVLQT1 associates with minK (IsK) protein to produce IKs channels (Barhanin et al., 1996; Sanguinetti et al., 1996), while human ether-a-go-go related gene (HERG) protein forms the pore-forming subunit of IKr channels (Curran et al., 1995; Sanguinetti et al., 1995; Trudeau et al., 1995). The Chromanol derivative 293B was found to be a potent blocker not only for IKs in guinea-pig ventricular cells but also for the membrane current through the IsK proteins heterologously expressed in Xenopus oocytes (Busch et al., 1996; Suessbrich et al., 1996). Subsequent studies have confirmed the highly selective blocking action of 293B on IKs in many types of isolated cardiac cells (Bosch et al., 1998; Fujisawa et al., 2000; Ono et al., 2000; Lei et al., 2002). As for molecular basis for 293B action on IKs channels, it has been suggested that KvLQT1 protein represents a relevant target for the actions of 293B (Loussouarn et al., 1997) while minK protein also acts allosterically to facilitate 293B binding to KvLQT1 protein (Busch et al., 1997; Lerche et al., 2000). In the present study we characterized the blocking action of 293B on IKs under control conditions and during exposure to β-adrenergic agonist isoprenaline in isolated guinea-pig SA node cells using the whole-cell patch-clamp technique. The results demonstrate that 293B is a potent and fully reversible blocker of IKs in the absence and presence of isoprenaline and that 293B preferentially affects IKs channels in an open state.
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Blocking action of Chromanol 293B on the slow component of delayed rectifier K(+) current in guinea-pig sino-atrial node cells.
British journal of pharmacology, 2002Co-Authors: Weiguang Ding, Futoshi Toyoda, Hiroshi MatsuuraAbstract:In guinea-pig sino-atrial (SA) node cells the delayed rectifier K+ current (IK) is composed of rapidly and slowly activating components of IK (IKr and IKs, respectively). The present study was undertaken to characterize the blocking action of the Chromanol derivative 293B on IKs in guinea-pig SA node cells using whole-cell patch-clamp technique. Bath application of 293B blocked IKs, elicited by 4-s depolarizing voltage pulses from a holding potential of −50 mV, under conditions in which the L-type Ca2+ current (ICa,L) and IKr were inhibited; the effect was concentration-dependent with an IC50 of 5.3 μM, when evaluated by the decrease in the amplitude of IKs tail current following 4-s depolarizing voltage steps to +50 mV. The 293B block of IKs progressed with time during depolarizing voltage steps with a more rapid block at higher concentrations. The block of IKs by 293B was fully reversed within a few minutes after washing off the drug, even when a maximal effect (a nearly full block) was achieved at high drug concentration (50 μM). Bath application of 293B at 50 μM greatly and reversibly reduced the amplitude of IKs which is maximally stimulated by β-adrenergic agonist isoprenaline (1 μM), while the degree of 293B block of the isoprenaline-stimulated IKs was slightly but significantly smaller than that of non-stimulated IKs (94.0±0.98% block, n=6 vs 99.4±0.45% block, n=6; P