Lengthening Of Repolarization Research Articles

Methadone Blockade of Cardiac Inward Rectifier K+ Current Augments Membrane Instability and Amplifies U Waves on Surface ECGs: A Translational Study.

BackgroundMethadone is associated with a disproportionate risk of sudden death and ventricular tachyarrhythmia despite only modest inhibition of delayed rectifier K+ current (I Kr), the principal mechanism of drug‐associated arrhythmia. Congenital defects of inward rectifier K+ current (I K1) have been linked to increased U‐wave amplitude on ECG and fatal arrhythmia. We hypothesized that methadone may also be a potent inhibitor of I K1, contributing to delayed repolarization and manifesting on surface ECGs as augmented U‐wave integrals.Methods and ResultsUsing a whole‐cell voltage clamp, methadone inhibited both recombinant and native I K1 with a half‐maximal inhibitory concentration IC50) of 1.5 μmol/L, similar to that observed for I Kr block (half‐maximal inhibitory concentration of 2.9 μmol/L). Methadone modestly increased the action potential duration at 90% repolarization and slowed terminal repolarization at low concentrations. At higher concentrations, action potential duration at 90% repolarization lengthening was abolished, but its effect on terminal repolarization rose steadily and correlated with increased fluctuations of diastolic membrane potential. In parallel, patient ECGs were analyzed before and after methadone initiation, with 68% of patients having a markedly increased U‐wave integral compared with premethadone (lead V3; mean +38%±15%, P=0.016), along with increased QT and TPeak to TEnd intervals, likely reflective of I Kr block.ConclusionsMethadone is a potent I K1 inhibitor that causes augmentation of U waves on surface ECG. We propose that increased membrane instability resulting from I K1 block may better explain methadone’s arrhythmia risk beyond I Kr inhibition alone. Drug‐induced augmentation of U waves may represent evidence of blockade of multiple repolarizing ion channels, and evaluation of the effect of that agent on I K1 may be warranted.

Prolonged alloxan diabetes mellitus in rabbits, an experimental model associated with increased susceptibility to reperfusion ventricular tachyarrhythmias

Introduction Diabetes mellitus (DM) increases the risk of ventricular arrhythmias and sudden cardiac death in patients with coronary artery disease. However, experimental studies often yield inconsistent results concerning arrhythmic outcomes in DM. Moreover, some studies reported that DM confers antiarrhythmic protection. We hypothesized that the duration of experimental diabetic conditions might be crucial in the DM-related arrhythmogenesis and evaluated myocardial electrical remodeling and susceptibility to ventricular tachyarrhythmias in rabbits with DM of different duration in the experimental ischemia/reperfusion model. Methods Ventricular epicardial contact potential 64-lead mapping and arrhythmia susceptibility burst-pacing testing were performed in 43 healthy and 55 diabetic (alloxan model) anesthetized rabbits undergoing 15-min left anterior descending coronary artery occlusion, followed by 15-min reperfusion. DM duration was from 28 to 76 days (median 42 days, interquartile range (IQR) 36-54 days). Results During ischemia, arrhythmia inducibility did not differ between the groups (14 out of 55 vs 7 out of 43 in the DM and control groups, respectively, p=0.272), but the number of reperfusion ventricular tachycardias and/or ventricular fibrillations (VT/VFs) was higher in the DM group (14 out of 55) as compared to control (3 out of 43, p=0.017). In the diabetic animals, the DM duration was an independent predictor of reperfusion VT/VF in logistic regression analysis adjusted for glucose concentration (OR 1.060; 95% CI 1.006-1.117; p = 0.029). We compared preischemic electrophysiological parameters in the control group, and groups with short and prolonged DM (cut-point 42 days of DM). The groups did not differ in dispersion of repolarization, time of epicardial activation breakthrough, duration of epicardial and total ventricular activation. Only duration of activation-repolarization intervals (ARIs, a surrogate for action potential duration) differed between the groups being increased in the prolonged DM group (Figure). Among the mapping parameters, DM duration was associated with the prolongation of total ventricular activation duration (B 0.152; 95% CI 0.049-0.255; p=0.005) and activation-repolarization intervals (ARIs) (B 0.900; 95% CI 0.315-1.484; p=0.003). The prolonged ARI was the only mapping characteristic predicting reperfusion VT/VF development in logistic regression analysis (OR 1.028; 95% CI 1.009-1.048; p = 0.004) and ROC curve analysis (AUC 0.781, p=0.001) with the optimal cut-off value ARI > 120 ms (sensitivity 0.80, specificity 0.75). Conclusions Prolongation of alloxan DM leads to the progressive lengthening of repolarization and increase in the reperfusion VT/VF inducibility.

Cardiac electrophysiological effects of ibuprofen in dog and rabbit ventricular preparations: possible implication to enhanced proarrhythmic risk.

Ibuprofen is a widely used nonsteroidal anti-inflammatory drug, which has recently been associated with increased cardiovascular risk, but its electrophysiological effects have not yet been properly studied in isolated cardiac preparations. We studied the effects of ibuprofen on action potential characteristics and several transmembrane ionic currents using the conventional microelectrode technique and the whole-cell configuration of the patch-clamp technique on cardiac preparations and enzymatically isolated ventricular myocytes. In dog (200 µM; n= 6) and rabbit (100 µM; n= 7) papillary muscles, ibuprofen moderately but significantly prolonged repolarization at 1Hz stimulation frequency. In dog Purkinje fibers, repolarization was abbreviated and maximal rate of depolarization was depressed in a frequency-dependent manner. Levofloxacin (40 µM) alone did not alter repolarization, but augmented the ibuprofen-evoked repolarization lengthening in rabbit preparations (n= 7). In dog myocytes, ibuprofen (250 µM) did not significantly influence IK1, but decreased the amplitude of Ito and IKr potassium currents by 28.2% (60mV) and 15.2% (20mV), respectively. Ibuprofen also depressed INaL and ICa currents by 19.9% and 16.4%, respectively. We conclude that ibuprofen seems to be free from effects on action potential parameters at lower concentrations. However, at higher concentrations it may alter repolarization reserve, contributing to the observed proarrhythmic risk in patients.

Potential role of potassium currents in the repolarization reserve: the importance of cardiac repolarization reserve in safety pharmacology

E-mail: jost.norbert@gmail.com Cardiac repolarization is a delicate process and the determinants of repolarization in various species are poorly understood. This study compared the contribution of IK1, IKr and IKs to cardiac repolarization in canine and human ventricular preparations by applying conventional microelectrode, whole cell patch-clamp and molecular biological techniques. Pharmacological inhibition of IKr evokes modest prolongation of repolarization in the dog ventricle, while it largely lengthens it in the human. These results suggest that in human, in addition to its known effect to establish the resting membrane potential, IK1 is contributing only to the repolarization reserve, while in the dog, IK1 also plays a role to secure the normal repolarization. Therefore, the smaller IK1 in human comparing to the dog makes the ventricle more susceptible to repolarization lengthening in the human than in the dog. This should be taken into consideration when pharmacological results from the dog studies are extrapolated to the human, i.e. the effect on repolarization of drugs potentially blocking IKr/HERG channels can be underestimated in the human based on experiments performed in the dog. We conclude that humans show much greater repolarizationdelaying effects of IKr-block than dogs, because of lower repolarization-reserve contributions from IK1 and IKs. These results are relevant to understanding species-specific determinants of repolarization and emphasize the limitations of animal models for the human disease.

Impairment of trafficking by downregulation of an anchor protein: Novel insights into additional mechanisms responsible for heart failure

In chronic heart failure, a number of these changes have been described. 2,3 Electrically, the impulse is not only slowed but often the duration of the cardiac action potential is prolonged as well. Reduced expression in the macromolecules controlling potassium channels and a more prominent late sodium channel current have been described to explain the lengthening of repolarization. Structurally, the heart is dilated and there is increased fibrous tissue. In the control of the intracellular calcium transient, the release of calcium of the sarcoplasmic reticulum (SR) and the reuptake by the SR have been the targets of both an altered protein expression and phosphorylation status, in particular for the ryanodine receptor, the SR Ca-ATPase (SERCA), and phospholamban. In the sarcolemma, the function of the Na/Ca exchange, responsible for the removal of Ca from the cell, has been described to be increased. However, the expression of the major calcium subunit (Cav1.2) and the ICaL current (its function) are less well understood in heart failure. Several reports have noted no change in expression or wholecell function. However, evidence was presented that the number of channels in the membrane is reduced while the channel activity may be increased because of altered phosphorylation. 4,5 More recently, changes in the expression of the beta-2 subunit also have been linked to altered channel functions. 6 The current study by Hong et al 7 supports earlier

Effects of diclofenac on ventricular muscle repolarization: proarrhythmic implications

Results Diclofenac (30 μM) decreased the amplitude of rapid (IKr) and slow (IKs) delayed rectifier and L-type calcium currents (ICa) without influencing transient outward (Ito) and inward rectifier (IK1) potassium currents. The action potential was slightly lengthened in ventricular muscle but shortened in Purkinje fibres by diclofenac (20 μM). The maximum upstroke velocity (Vmax) was decreased in both preparations. Larger repolarization lengthening was observed when repolarization reserve was impaired by previous BaCl2 application. Diclofenac (3 mg/kg) did not prolong the QTc interval, while the potassium channel blocker dofetilide (25 μg/kg) significantly lengthened QTc in anaesthetized rabbits. The combination of diclofenac and dofetilide significantly prolonged QTc. 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 led to a significant increase in the incidence of TdP.

Enhanced Repolarization Capacity: New Potential Antiarrhythmic Strategy Based on hERG Channel Activation

The delayed rectifier potassium current (I(K)) is the major outward current responsible for ventricular repolarization in cardiac tissues. Based on kinetic properties and drug sensitivity it is composed of a slow (I(Ks)) and a rapid (I(Kr)) component, the latter is mediated by hERG channels. Suppression of IKr is the common mechanism of action of all class III antiarrhythmics, causing prolongation of the refractory period. However, lengthening of repolarization - either by a pathological factor or due to a pharmacological intervention - threatens with an increased risk of EAD generation and the concomitant sudden cardiac death. Therefore, a new potential anti-arrhythmic strategy, based on augmentation of the repolarization reserve, has been emerged. Recently a new class of compounds has been introduced as activators of the hERG channel. In this article we systematically review the chemical structures found to enhance IKr. Since the majority of previous experiments were performed in expression systems or in rodent cardiac preparations (neither is relevant to the human heart), in the second part of this article we present some results obtained with NS1643, the best examined hERG activator, in canine ventricular cardiomyocytes. This preparation is believed to have electrophysiological parameters most resembling those of human. NS1643 shortened the duration of canine ventricular action potential and was shown to interact with several transmembrane ion currents, including I(Ca), I(Kr), I(Ks), and I(to). However, the action potential shortening effect of NS1643 is likely related to inhibition of ICa, in addition to the enhancement of IKr. Although the multiple ion channel activity of NS1643 may carry proarrhythmic risk, the rationale of antiarrhythmic strategy based on I(Kr) activation is not questioned.

The p75 neurotrophin receptor, semaphorins, and sympathetic traffic in the heart

the sympathetic and parasympathetic branches of the autonomic nervous system control cardiac function through the coordinated activity generated by neurons within the intracardiac autonomic ganglia and central nervous system (3). Activation of the sympathetic efferent projections to the heart increases heart rate, modifies the pattern and conduction velocity of the impulse through the heart, and augments both atrial and ventricular contractility while hastening myocardial relaxation. In the vasculature, the sympathetic nervous system (SNS) reduces venous capacitance and constricts resistance vessels, increasing blood pressure. Conversely, the parasympathetic nervous system (PSNS) decreases heart rate and cardiac impulse conduction. More recent evidence has suggested that the PSNS may also affect ventricular function, indirectly by countering β-adrenergic action or directly via inhibition of L-type Ca2+ channels (34). A transient imbalance between these two branches can lead to increased heart rate and blood pressure when cardiac output is increased. When subnormal cardiac PSNS activity concomitant with sympathetic hyperactivation persists, such as after myocardial infarction, this disequilibrium may increase the risk for cardiac adverse events, including arrhythmias, hypertension, cardiac hypertrophy, and, ultimately, heart failure. This condition is called “autonomic neural remodeling” and can greatly contribute to the induction of ventricular fibrillation, thus increasing the patient's susceptibility to sudden cardiac death (41, 47). It is plausible that neurotrophic factors, target organ-secreted proteins essential for the development and differentiation of neurons, are involved in the remarkable neuroplasticity exhibited by the SNS in the adult life, including autonomic remodeling after infarction and/or in the onset and progression of congestive heart failure (17, 30, 32).

Self‐augmentation of the lengthening of repolarization is related to the shape of the cardiac action potential: implications for reverse rate dependency

The aims of the present work were to study the mechanism of the reverse rate dependency of different interventions prolonging cardiac action potential duration (APD). The reverse rate-dependent lengthening effect of APD-prolonging interventions and the possible involvement of I(Kr) (rapid component of the delayed rectifier potassium current) and I(K1) (inward rectifier potassium current) were studied by using the standard microelectrode and the whole-cell patch-clamp techniques in dog multicellular ventricular preparations and in myocytes isolated from undiseased human and dog hearts. All applied drugs--dofetilide (1 micromol.L(-1)), BaCl(2) (10 micromol.L(-1)), BAY-K-8644 (1 micromol.L(-1)), veratrine (1 microg.mL(-1))--lengthened APD in a reverse rate-dependent manner regardless of their mode of action, suggesting that reverse rate dependency may not represent a specific mechanism of APD prolongation. The E-4031-sensitive current (I(Kr)) and the Ba(2+)-sensitive current (I(K1)) were recorded during repolarizing voltage ramps having various steepness and also during action potential waveforms with progressively prolonged APD. Gradually delaying repolarization results in smaller magnitude of I(Kr) and I(K1) currents at an isochronal phase of the pulses. This represents a positive feedback mechanism, which appears to contribute to the reverse rate-dependent prolongation of action potentials. Action potential configuration may influence the reverse rate-dependent APD prolongation due to the intrinsic properties of I(Kr) and I(K1) currents. Drugs lengthening repolarization by decreasing repolarizing outward, or increasing depolarizing inward, currents are expected to cause reverse rate-dependent APD lengthening with high probability, regardless of which current they modify.

Newer Antiarrhythmic Agents for Atrial Fibrillation: Shall we Eventually do away with Proarrhythmia?

Despite advances in drug therapy for the treatment of atrial fibrillation (AF), there continues to be a need for antiarrhythmic agents that have improved safety and efficacy profile. Unfortunately, drugs that block the potassium channels or are multichannel blockers, although they may be effective antiarrhythmics, they delay repolarization and thus they confer a proarrhythmic effect by inducing torsade de pointes, a potentially lethal ventricular arrhythmia. Most newer antiarrhythmic drugs are potassium channel blockers and this limits their usefulness. A less toxic agent compared to amiodarone, the noniodinated analogue of amiodarone (dronedarone) is being investigated; however, it appears already unsafe in patients with heart failure. Future antiarrhythmic agents will probably be atrial-selective blocking agents without affecting repolarization in the ventricular myocardium and thus avoid ventricular proarrhythmia with its attendant life-threatening consequences. I N T R O D U C T I O N Despite advances in drug therapy for the treatment of atrial fibrillation (AF), there continues to be a need for antiarrhythmic agents that have improved safety and efficacy profile. The wavelength in the atrium plays a critical role in AF. The two fundamental mechanisms of antiarrhythmic drugs in terminating AF include slowing of conduction and lengthening of repolarization and refractoriness. In the wake of the CAST trial demonstrating the proarrhythmic properties of agents with selectivity for sodium channels, when used as antiarrhythmic drugs in patients with significant underlying structural heart disease, attention switched to drugs inhibiting potassium channels. They terminate and/or prevent AF by lengthening action potential duration and the effective refractory period. Unfortunately, drugs that delay repolarization can induce polymorphic ventricular tachycardia in the form of torsade de pointes, a potentially lethal proarrhythmic effect. RevIew 2 Department of Cardiology, Evagelismos General Hospital of Athens, Athens, Greece HOSPITAL CHRONICLES 2008, 3(1): 25–28 Correspondence to: Anthony Sideris, MD 2nd Department of Cardiology Evagelismos Hospital Athens, Greece E-mail: asideris@hol.gr Key wORDS: antiarrhythmic agents; atrial fibrillation; proarrhythmia; torsade de pointes; atrial selective

Acquired long QT syndrome: Unequal regression of Amiodarone-induced repolarization lengthening

We describe full exposure of an acquired Long QT Syndrome (aLQTS) in an elderly female patient on long-term Amiodarone treatment. We propose that the aLQTS is the result of combined block of the rapid (I Kr) and delayed (I Ks) components of the outward potassium current (I K), translated to the ECG in a (more than expected) prolonged QT interval, an augmented transmural dispersion of repolarization (TDR) and an interrupted T wave. The unequal regression of repolarization lengthening made possible to individualize I K current components in the inscription of the interrupted T wave, which argues against the U wave as a separate entity. Silent ion channel gene mutations or polymorphisms and downregulation of β-adrenergic activation of I Ks may underlie the unusual repolarization behaviour. The unequal regression over time of Amiodarone-induced repolarization lengthening could have clinical significance.

Theoretical possibilities for the development of novel antiarrhythmic drugs.

One possible mechanism of action of the available K-channel blocking agents used to treat arrhythmias is to selectively inhibit the HERG plus MIRP channels, which carry the rapid delayed rectifier outward potassium current (I(Kr)). These antiarrhythmics, like sotalol, dofetilide and ibutilide, have been classified as Class III antiarrhythmics. However, in addition to their beneficial effect, they substantially lengthen ventricular repolarization in a reverse-rate dependent manner. This latter effect, in certain situations, can result in life-threatening polymorphic ventricular tachycardia (torsades de pointes). Selective blockers (chromanol 293B, HMR-1556, L-735,821) of the KvLQT1 plus minK channel, which carriy the slow delayed rectifier potassium current (I(Ks)), were also considered to treat arrhythmias, including atrial fibrillation (AF). However, I(Ks) activates slowly and at a more positive voltage than the plateau of the action potential, therefore it remains uncertain how inhibition of this current would result in a therapeutically meaningful repolarization lengthening. The transient outward potassium current (I(to)), which flows through the Kv 4.3 and Kv 4.2 channels, is relatively large in the atrial cells, which suggests that inhibition of this current may cause substantial prolongation of repolarization predominantly in the atria. Although it was reported that some antiarrhythmic drugs (quinidine, disopyramide, flecainide, propafenone, tedisamil) inhibit I(to), no specific blockers for I(to) are currently available. Similarly, no specific inhibitors for the Kir 2.1, 2.2, 2.3 channels, which carry the inward rectifier potassium current (I(kl)), have been developed making difficult to judge the possible beneficial effects of such drugs in both ventricular arrhythmias and AF. Recently, a specific potassium channel (Kv 1.5 channel) has been described in human atrium, which carries the ultrarapid, delayed rectifier potassium current (I(Kur)). The presence of this current has not been observed in the ventricular muscle, which raises the possibility that by specific inhibition of this channel, atrial repolarization can be lengthened without similar effect in the ventricle. Therefore, AF could be terminated and torsades de pointes arrhythmia avoided. Several compounds were reported to inhibit I(Kur)(flecainide, tedisamil, perhexiline, quinidine, ambasilide, AVE 0118), but none of them can be considered as specific for Kv 1.5 channels. Similarly to Kv 1.5 channels, acetylcholine activated potassium channels carry repolarizing current (I(KAch)) in the atria and not in the ventricle during normal vagal tone and after parasympathetic activation. Specific blockers of I(KAch) can, therefore, also be a possible candidate to treat AF without imposing proarrhythmic risk on the ventricle. At present several compounds (amiodarone, dronedarone, aprindine, pirmenol, SD 3212) were shown to inhibit I(KAch) but none of them proved to be selective. Further research is needed to develop specific K-channel blockers, such as I(Kur)and I(KAch) inhibitors, and to establish their possible therapeutic value.

Dual rate-dependent cardiac electrophysiologic effects of haloperidol: slowing of intraventricular conduction and lengthening of repolarization.

Treatment with the neuroleptic agent haloperidol is sometimes associated with serious cardiac arrhythmias. The proarrhythmic potential of haloperidol may be linked to the drug's rate-dependent modulation of cardiac impulse conduction and repolarization. Herein these heart rate-dependent electrophysiologic actions of haloperidol are investigated in vivo. In anesthetized guinea pigs, haloperidol (0.02 mg/kg/min intravenously) produced significant rate-dependent slowing of intraventricular conduction. On abruptly changing the driving cycle length from 500 ms to 300 ms, conduction slowing rapidly reached a new steady state with a rate constant of 0.80 per beat +/- 0.07. The time course of recovery from conduction slowing on interruption of rapid pacing at a cycle length of 250 ms was well described by two time constants, tau(rec1) = 18.9 ms +/- 8.0 and tau(rec2) = 141.8 ms +/- 87.1, suggesting rapid dissociation of the drug from the Na+ channel. During prolonged stimulation, conduction slowing had a biphasic dependence on heart rate: for each 10-bpm increment in heart rate, conduction slowing increased by 7.9% at rates <220 bpm and by 17% at rates >220 bpm. At all tested cycle lengths, haloperidol caused a significant lengthening of Q(T) intervals, which was inversely dependent on heart rate. Numeric analysis suggested that the excessive increase in conduction slowing at rates >220 bpm was due to the drug's Q(T)-prolonging effect, indicating that, at short cycle lengths, the impulses encroached on the refractory period. Thus, in vivo, haloperidol slows intracardiac conduction with rapid on/off kinetics, comparable to the class I antiarrhythmic agent lidocaine. The Q(T) prolongation by haloperidol may lead to an excessive conduction slowing at high heart rates.

Effects of thoracic epidural anesthesia with and without autonomic nervous system blockade on cardiac monophasic action potentials and effective refractoriness in awake dogs.

The effects of thoracic epidural anesthesia (TEA) on myocardial repolarization and arrhythmogenicity are only incompletely understood. This is primarily because of the lack of appropriate experimental models. In most of the studies performed thus far, TEA was used in anesthetized animals. Baseline anesthesia itself may have modified the effects of TEA. This study investigates right atrial and ventricular repolarization by recording monophasic action potentials after TEA in awake dogs. The authors hypothesized that an antiarrhythmic role of TEA exists, which may be related to a direct effect of TEA on myocardial repolarization. The hypothesis was tested in an in vivo canine model, in which atrial and ventricular myocardial action potential duration and refractoriness are recorded by means of monophasic action potential catheters. Thoracic epidural anesthesia significantly increased ventricular monophasic action potential duration for cycle lengths shorter than 350 ms. Changes in monophasic action potential duration were paralleled by a concomitant prolongation of effective refractory period (ERP) at higher rates so that the ratio of ERP to action potential duration was unaffected. This model helps to study the role of TEA on ventricular repolarization and arrhythmogenicity. Because lengthening of repolarization and prolongation of refractoriness may, in some circumstances, be antiarrhythmic, TEA may be protective against generation of ventricular arrhythmias mediated, e.g., by increased sympathetic tone. The results also imply that the beneficial role of TEA might be stronger at the ventricular site as compared with the atrium. At atrial sites there was only a trend toward prolongation of repolarization even at short cycle lengths.

Effect of disopyramide on potassium currents in rabbit ventricular myocytes.

The effects of disopyramide (1-30 microM) on the 4-aminopyridine sensitive transient outward current (I(to)), on the rapid component of the delayed rectifier potassium current (I(Kr)) and on the inward rectifier potassium current (I(kl)) were studied in single rabbit ventricular myocytes at 35 degrees C by applying the whole-cell configuration of the patch clamp technique. Disopyramide significantly decreased the amplitude of I(to) (from 1510 +/- 122 pA at control to 1015 +/- 21 pA after 30 microM disopyramide at +50 mV; n = 5). This effect was not voltage- or use-dependent. Disopyramide (10 microM) influenced neither the recovery from inactivation of I(to) nor the steady-state inactivation curve. The drug dose dependently decreased the time constant of the fast component of the decay of I(to) (tau(f) = 6.41 +/- 0.25 ms, n = 24 for control; and 2.20 +/- 0.38 ms, n = 5 after 30 microM disopyramide at +50 mV). The fractional block caused by 30 microM disopyramide as a function of time was well fitted by a single exponential function with time constant of 1.48 +/- 0.18 ms (n = 5), most likely reflecting the binding kinetics of the drug to the open channel. The offset kinetics of the drug was estimated by using a double-pulse protocol and its time constant was 3.9 +/- 0.5 ms. Disopyramide (30 microM) did not influence significantly the onset of inactivation measured at -20 mV. The estimated EC50 value for the I(to) block by disopyramide was 14.1 microM. Our results are consistent with an open-channel block of I(to) by disopyramide, however, a weak, drug-induced increase of the rate of inactivation and a moderate tonic block cannot be excluded. The amplitude of the outward tail current attributed to I(Kr) was depressed dose dependently by disopyramide (after clamping the cells back to the holding potential from +30 mV, 139.5 +/- 10.9 pA for control, and 30.7 +/- 3.2 pA in the presence of 10 microM disopyramide; n = 11). The estimated EC50 was 1.8 microM. I(to) is thus less sensitive to disopyramide than I(Kr). I(kl) was not influenced significantly by disopyramide, even when applied in the highest tested concentration (30 microM). It is concluded that in rabbit ventricular myocytes disopyramide blocks not only I(Kr), but also I(to), both of which may play an important role in the well established repolarization lengthening and antiarrhythmic effects of the drug.

Frequency-dependent Cardiac Electrophysiologic Effects of Tedisamil: Comparison With Quinidine and Sotalol.

BACKGROUND: Tedisamil is a potent bradycardiac/antiischemic drug known to lengthen cadiac repolarization by blocking various potassium channels. Recent in vivo experiments revealed that it is an antiarrhythmic agent. It was therefore of interest to compare the cellular electrophysiologic effects of tedisamil with those of quinidine and sotalol in isolated cardiac preparations. METHODS AND RESULTS: The conventional microelectrode technique was applied in isolated dog cardiac Purkinje and ventricular muscle fibers and in rabbit left atrial muscle. Tedisamil (1 µM) and sotalol (30 µM) lengthened, while quinidine (10 µM) shortened action potential duration in dog Purkinje fibers. The phase 1 repolarization was delayed by tedisamil and quinidine and not changed by sotalol. In dog ventricular muscle and in rabbit atrial muscle, all three drugs studied lengthened repolarization. In dog Purkinje fiber, tedisamil and sotalol lengthened action potential duration more at slow than at high stimulation frequency (reverse use-dependence). In dog ventricular muscle fibers, the effect of the drugs was not clearly frequency dependent. In rabbit atrial muscle fibers, the quinidine-evoked repolarization lengthening was most pronounced at intermediate cycle lengths (500-1000 ms). Tedisamil and quinidine but not sotalol depressed the maximal rate of depolarization (V(max)), which depended on the stimulation frequency (use-dependence). The nature of the use-dependent V(max) block differed between quinidine and tedisamil. Quinidine decreased V(max) at a relatively wide range of stimulation frequencies whle tedisamil. Quinidine decreased V(max) at a relatively wide range of stimulation frequencies while tedisamil decreased V(max) largely at high rate of stimulation. Tedisamil and quiinidine prevented or decreased the pinacidil-evoked action potential shortening in dog ventricular muscle, suggesting block of the ATP-dependent potassium channels (I(KATP)), while with sotalol such effect was not observed. CONCLUSIONS: Although tedisamil, quinidine, and sotalol are known to lengthen the QT interval, their cellular electrophysiologic effects substantially differ. Tedisamil lengthens repolarization and prevents pinacidil-evoked action potential duration shortening, suggesting I(K(ATP)) blockade. Its effect on the V(max) is limited mostly to fast heart rate. These electrophysiologic effects of tedisamil resemble those of chronic amiodarone treatment.

Effects of Nonsedating Antihistamine, Astemizole, on thein SituCanine Heart Assessed by Cardiohemodynamic and Monophasic Action Potential Monitoring

The possible mechanisms of cardiac adverse effects of astemizole were studied using a halothane-anesthetizedin vivocanine model under the cardiohemodynamic and monophasic action potential monitoring. A dose of 0.3 mg/kg of iv astemizole (n= 7), which is close to the recommended dose for clinical use, showed a bradycardic effect and a reversed use-dependent lengthening of repolarization. The increase in the repolarization was greater than in the effective refractory period. These effects persisted even when the plasma drug concentration became undetectable. Additional administration of 3.0 mg/kg of iv astemizole (n= 7) decreased the mean blood pressure, suppressed the cardiac contraction and conduction, and induced early after depolarization-like potential in addition to the qualitatively similar effects compared to those observed by the lower dose. The decrease of the plasma concentration of astemizole followed the pattern predicted by the two-compartment theory of pharmacokinetics, but the drug concentration in the cardiac muscle was estimated to be more than 100 times greater than that in plasma. Our study emphasizes that each cardiac consequence of astemizole overdose may be related to proarrhythmic effects and the monitoring of plasma drug concentration will be less helpful in predicting the cardiac adverse effects of astemizole. The results provide some insights into the clinical cardiotoxicity of astemizole. Drugs or interventions inducing positive chronotropic, inotropic, and dromotropic effects can become good candidates for the treatment of astemizole intoxication, which may attenuate the cardiac effects of astemizole including the lengthening of repolarization.

Transient T wave abnormalities after cessation of ventricular preexcitation: memory of what?

(1) Ventricular preexcitation causes both secondary and primary T wave changes. The secondary changes disappear immediately after cessation of preexcitation (ablation of accessory pathways) and unmask the primary T wave changes that regress within days, weeks, or months. (2) The pattern of primary T wave change produced by ventricular preexcitation depends on the location of the accessory pathway connections. The septal and posterior connections are associated with more prominent anteriorly directed T wave deflections and deviation of the T wave vector superiorly. The left lateral connections are associated with rightward deviation of the T wave vector in the frontal plane. (3) The primary T wave abnormalities are believed to be caused by local lengthening of repolarization, but the site of the postulated abnormalities needs to be established. (4) The persistence and slow dissipation of the primary T wave change induced by ventricular pacing, left bundle branch block, and presumably ventricular preexcitation have been attributed to the memory of past events. The nature of these events is not known. Several in vitro models demonstrated phenomena of gradual adjustment of ventricular action potential duration to change in cycle length, or to altered pattern of stimulation, but none of such models has mimicked the long-lasting regression of T wave abnormalities. (5) The terms T wave memory and pseudoprimary repolarization changes lack specificity and are unnecessary additions to the electrocardiographic vocabulary.

Cardiac electrophysiology, arrhythmogenic mechanisms and roentgen contrast media.

Contrast media (CM) affect normal cardiac electrophysiology when injected into the coronary arteries. High-osmolality CM cause more pronounced electrophysiological effects than do low-osmolality CM. Further, both high- and low-osmolality ionic CM have more pronounced effects than the nonionic CM. The CM-induced electrophysiological effects involve regional disturbances of depolarization and repolarization, thereby causing disturbances of impulse conduction as well as dispersion of refractoriness. Recent experimental studies have demonstrated that the addition of sodium or a balanced electrolyte supplement to nonionic CM reduces the risk of ventricular fibrillation (VF), particularly when the CM is injected in a wedged catheter situation. The reduced risk of VF may be due to the small and transient lengthening of repolarization seen in the CM-perfused area of the myocardium. Iodixanol, which is an isotonic nonionic dimer supplemented with NaCl and CaCl(2), is as well tolerated as iohexol during free coronary flow. However, when flow is restricted, such as when CM is injected through a wedged catheter, the risk of VF is less with iodixanol than with iopamidol, iohexol and ioxaglate.

Electrophysiologic properties of sotalol and d-sotalol. A current view.

Although discovered more than two decades ago, the clinical applications of sotalol are still a matter of debate. Together with amiodarone, sotalol is considered a prototype of a new class of antiarrhythmic agents characterized by repolarization-prolonging effects (class III). Lengthening of repolarization is associated with an increase in the effective refractory period of cardiac tissues. There is no change in the maximum rate of rise during phase 0, a finding that supports the lack of sotalol effect on the fast sodium channel. The electrophysiologic action of the drug in humans provides evidence for direct cardiac effects of sotalol in addition to beta blockade. The beta-blocking properties play a major role in the sinus-rate slowing and lengthening of the atrioventricular nodal conduction time observed after sotalol administration. However, the drug also prolongs refractoriness in atria, His-Purkinje tissue, ventricular muscle and accessory atrioventricular connections. These latter changes are absent or minimal with conventional beta blockers and are likely to reflect sotalol-induced prolongation of cardiac repolarization. They result in an increase in the QT interval, an effect that is dose-dependent and more marked during chronic therapy. The dextrorotatory isomer, d-sotalol, shares a similar electrophysiologic profile. Lengthening of repolarization in cardiac cells following d-sotalol is of the same magnitude as that produced by the levoisomer. This finding provides further evidence for a class III action of sotalol, as the dextroisomer is almost devoid of beta-blocking properties. In humans, the electrical effects of both drugs are similar. However, d-sotalol-induced changes in sinus rate and atrioventricular nodal conduction are modest.(ABSTRACT TRUNCATED AT 250 WORDS)