Antiarrhythmic Compound Research Articles

Antiarrhythmic and electrophysiological effects of GYKI-16638, a novel N-(phenoxyalkyl)- N-phenylalkylamine, in rabbits

The effect of N-[4-[2- N-methyl- N-[1-methyl-2-(2,6-dimethylphenoxy)ethylamino]-ethyl]-phenyl]-methanesulfonamide.hydrochloride (GYKI-16638; 0.03 and 0.1 mg/kg, i.v.), a novel antiarrhythmic compound, was assessed and compared to that of d-sotalol (1 and 3 mg/kg, i.v.) on arrhythmias induced by 10 min of coronary artery occlusion and 10 min of reperfusion in anaesthetized rabbits. Also, its cellular electrophysiological effects were studied in rabbit right ventricular papillary muscle preparations and in rabbit single isolated ventricular myocytes. In anaesthetized rabbits, intravenous administration of 0.03 and 0.1 mg/kg GYKI-16638 and 1 and 3 mg/kg d-sotalol significantly increased survival during reperfusion (GYKI-16638: 82% and 77%, d-sotalol: 75% and 83% vs. 18% in controls, P<0.05, respectively). GYKI-16638 (0.1 mg/kg) significantly increased the number of animals that did not develop arrhythmias during reperfusion (46% vs. 0% in controls, P<0.05). In isolated rabbit right ventricular papillary muscle, 2 μM GYKI-16638, at 1 Hz stimulation frequency, lengthened the action potential duration at 50% and 90% repolarization (APD 50–90) without influencing the resting membrane potential and action potential amplitude (APA). It decreased the maximal rate of depolarization ( V max) in a use-dependent manner. This effect was statistically significant only at stimulation cycle lengths shorter than 700 ms. The offset kinetics of this V max block were relatively rapid, the corresponding time constant for recovery of V max was 328.2±65.0 ms. In patch-clamp experiments, performed in rabbit ventricular myocytes, 2 μM GYKI-16638 markedly depressed the rapid component of the delayed rectifier outward and moderately decreased the inward rectifier K + current without significantly altering the slow component of the delayed rectifier and transient outward K + currents. These results suggest that in rabbits, GYKI-16638 has an in vivo antiarrhythmic effect, comparable to that of d-sotalol, which can be best explained by its combined Class I/B and Class III actions.

Structure-effect relationships of amiodarone analogues on the inhibition of thyroxine deiodination.

Amiodarone (AMI) has proven to be a potent anti-arrhythmic compound. Due to the structural similarity between AMI and thyroid hormone, it is possible that the drug could inhibit the activity of the 5'-thyroxine-deiodinase. AMI analogues resulting from (1) dealkylation, (2) deiodination and (3) deamination were synthesised and used as inhibitors in an in vitro biotransformation reaction of thyroxine (T4) to 3,3',5'-triiodothyronine (T3). Using high-performance liquid chromatography and ultraviolet detection for quantifying T3, it was found that the 5'-T4 deiodinase type I was involved in the reaction. On separate occasions, AMI or an AMI analogue was added to the reaction as an inhibitor. All studied AMI analogues inhibited 5'-T4 deiodination competitively (Ki value range 25-360 microM). In the concentration range of 1-1000 microM, AMI and its N-desethylated, deiodinated analogues inhibited 5'-T4 deiodination very weakly. AMI analogues with a hydroxyl group at the 4-position were strong inhibitors. Moreover, diiodo-AMI analogues inhibited 5'-T4 deiodination more strongly than their corresponding monoiodo- or deiodinated derivatives. It is likely that the degraded products of AMI could be responsible for thyroid dysfunction toxicosis in AMI therapy.

Isoproterenol specifically modulates reverse rate-dependent effects of d,l-sotalol, d-sotalol, and dofetilide.

The modulation of antiarrhythmic and proarrhythmic properties of antiarrhythmic compounds by increased sympathetic activity is of experimental and clinical interest. However, the interaction of adrenergic stimulation with the rate-response pattern of class III antiarrhythmic agents is not well established. Using standard microelectrode techniques, we evaluated the effects of isoproterenol (iso) on the action of d,l-sotalol (d,l-sot), d-sotalol (d-sot), and dofetilide (dof) on action-potential parameters recorded from isolated canine cardiomyocytes. The cell-isolation procedure was performed from the endocardial layers of left ventricular myocardium from healthy beagle dogs. The following electrophysiologic parameters were recorded: resting membrane potential (RMP), action-potential amplitude (APA), action-potential duration at 90% repolarization (APD 90), and effective refractory period (ERP). After exposure to iso, the class III activity of d,l-sot was well maintained over the entire range of frequencies studied. In contrast, iso differentially antagonized the action of d-sot and dof. In comparison to dof, the class III action of d-sot was particularly sensitive to iso, predominantly at faster stimulation rates. Our observations demonstrate specific rate regulation of the class III action of d,l-sot, d-sot, and dof in response to adrenergic stimulation. The unfavorable rate-response pattern of d-sot compared with d,l-sot and dof might prove disadvantageous in high-catecholamine states.

Overview of trends in the control of cardiac arrhythmia: past and future

The current antiarrhythmic scene is changing, with striking successes in recent years in radiofrequency ablation and implantable devices for atrial and ventricular arrhythmia. This has necessitated a reorientation in drug therapy, which has also become necessary in light of the outcome of clinical trials showing that certain antiarrhythmic drugs increase rather than decrease mortality, despite the suppression of the arrhythmia for which they are administered. The decrease in the use of sodium-channel blockers has led to increasing reliance on other antiarrhythmic compounds. These have mainly been β-blockers and complex class III agents, such as sotalol and amiodarone, for atrial fibrillation and selective compounds such as flecainide and propafenone and pure class III compounds in patients with little or no heart disease. The major focus of pharmacologic therapy in ventricular arrhythmia is now in conjunction with the use of implantable cardioverter defibrillators (ICDs), although not all subsets of patients in whom these devices offer a survival advantage have been clearly defined. Two items of information are now compelling. First, β-blockers should be regarded as antiarrhythmic drugs in their own right. This is suggested by the outcome of a number of mortality trials in patients with cardiac failure. Second, when given in conjunction with amiodarone, β-blockers exert a synergistic effect in reducing mortality in patients with heart disease. This raises the issue of whether the most effective medical therapy for controlling life-threatening ventricular arrhythmia might be a combination regimen rather than amiodarone or sotalol alone. Thus, future clinical trials should aim at defining the most effective ICD–drug combinations with single as well as multiple agents (including β-blockers) with endpoints including reduction of ICD shocks as well as total mortality. The potential roles of complex compounds such as amiodarone and sotalol and pure class III agents are under intense investigation. How competitive these pure compounds are likely to be with the more versatile compounds (e.g., sotalol and amiodarone) or their derivatives is being studied in a variety of experimental and clinical models in the continued search for an ideal antifibrillatory and antiarrhythmic class of compounds.

Clinical organ toxicity of antiarrhythmic compounds: ocular and pulmonary manifestations

The history of antiarrhythmic therapy reveals these agents to be associated with a high incidence of toxicity. Although several agents have ocular effects, amiodarone is the most widely recognized for producing adverse effects in the eyes. Corneal microdeposits are almost ubiquitous in patients being treated with amiodarone. However, they are, for the most part, benign and produce no changes in visual acuity. Lack of microdeposits should prompt the physician to investigate whether there is a problem with drug absorption or adherence to therapy. Other effects on the eye have been reported including optic neuropathy, but no causal link has been proved with amiodarone. The population of patients treated with amiodarone often have ischemic disease and/or diabetes, which affect retinal and optic nerve health. Many antiarrhythmic agents also affect lung function. The frequent association of procainamide with a lupus-like syndrome, where half the cases develop pleural–pericardial involvement, may require discontinuation of that drug. Although β blockers and to a lesser degree, calcium antagonists, may cause bronchospasm in some patients, this is not usually a major clinical problem. Again, it is amiodarone that has the most widespread reputation for causing pulmonary toxicity. Although infrequent (<1% incidence), it generates the most fear as it is sometimes fatal. Because of the lack of a diagnostic “gold standard,” it is often overdiagnosed, placing patients at risk from overlooked congestive heart failure and infections and from recurrent arrhythmias after drug withdrawal. Patients with pre-existing pulmonary disease appear to be more at risk. Common features include indolent onset of cough, malaise and fever associated with patchy peripheral infiltrates, and severely decreased diffusion capacity. Several cases of pulmonary toxicity have had inordinately high serum desethylamiodarone to amiodarone ratios. Most cases recover with cessation of amiodarone therapy. Steroids are commonly used, but are of unproved efficacy. In terms of its toxicity, amiodarone remains the most feared of the antiarrhythmic agents. In the future, a better understanding of its pharmacokinetics, mechanisms of toxicity, and optimal dosing regimens should provide a possibility of better strategies for avoidance, early diagnosis, and more directed therapy of toxicities associated with amiodarone.

Electrophysiological characterization of BRL-32872 in canine Purkinje fiber and ventricular muscle: Effect on early after-depolarizations and repolarization dispersion

Amongst the different pharmacological approaches to the treatment of cardiac arrhythmias, compounds with multiple electrophysiological activities appear to exhibit a reduced adverse effect profile. BRL-32872 ( N-(3,4-dimethoxyphenyl)- N-[3[[2-(3,4-dimethoxyphenyl) ethyl] propyl]-4-nitrobenzamide hydrochloride) is a typical example of an antiarrhythmic agent with combined K + and Ca 2+ blocking actions. In this study, we investigated the effects of BRL-32872 on early after-depolarizations and on dispersion of repolarization. Action potentials were recorded either in canine cardiac Purkinje fibers alone or in preparations containing both ventricular muscle and the attached Purkinje fibers. In Purkinje fibers, BRL-32872 (0.3–10 μM) induced a bell-shaped concentration-dependent increase in action potential duration. At 90% of repolarization, the action potential was prolonged at concentrations up to 1 μM and was shortened when the concentration of BRL-32872 was further increased. In all 17 experiments, BRL-32872 did not cause early after-depolarizations in Purkinje fibers. On the contrary, BRL-32872 (3 μM) systematically suppressed early after-depolarizations induced by clofilium (4-chloro- N, N-diethyl- N-heptylbenzenebutanaminium tosylate, 1 μM), a selective inhibitor of the delayed rectifier K + current. A similar effect was observed once with 1 μM BRL-32872, a concentration able to prolong Purkinje fiber action potentials. Simultaneous recording of action potentials in ventricular and Purkinje preparations showed that increasing concentrations of BRL-32872 (0.3–10 μM) induced a limited increase in the difference of repolarization time between the two tissues. The selective K + channel inhibitor E-4031 ( N-(4-(1-[2-(6-methyl-2-pyridyl) ethyl]-4-piperidyl)-carbonyl] phenyl) methanesulfonamide dihydrochloride dihydrate) exhibited a significant concentration-dependent increase in dispersion of repolarization. We conclude from the present results that the Ca 2+ blocking activity of BRL-32872 (i) prevents the occurrence of early after-depolarizations associated with action potential prolongation and (ii) limits an excessive increase in action potential duration heterogeneity. These electrophysiological features might represent the basis for antiarrhythmic compounds with reduced proarrhythmic profile.

Functional Analysis of a Mouse Brain Elk-Type K+Channel

Members of the Ether à go-go (Eag) K+ channel subfamilies Eag, Erg, and Elk are widely expressed in the nervous system, but their neural functions in vivo remain largely unknown. The biophysical properties of channels from the Eag and Erg subfamilies have been described, and based on their characteristic features and expression patterns, Erg channels have been associated with native currents in the heart. Little is known about the properties of channels from the Elk subfamily. We have identified a mouse gene, Melk2, that encodes a predicted polypeptide with 48% amino acid identity to Drosophila Elk but only 40 and 36% identity with mouse Erg (Merg) and Eag (Meag), respectively. Melk2 RNA appears to be expressed at high levels only in brain tissue. Functional expression of Melk2 in Xenopus oocytes reveals large, transient peaks of current at the onset of depolarization. Like Meag currents, Melk2 currents activate relatively quickly, but they lack the nonsuperimposable Cole-Moore shift characteristic of the Eag subfamily. Melk2 currents are insensitive to E-4031, a class III antiarrhythmic compound that blocks the Human Ether-à-go-go-Related Gene (HERG) channel and its counterpart in native tissues, IKr. Melk2 channels exhibit inward rectification because of a fast C-type inactivation mechanism, but the slower rate of inactivation and the faster rate of activation results in less inward rectification than that observed in HERG channels. This characterization of Melk currents should aid in identification of native counterparts to the Elk subfamily of channels in the nervous system.

Pro: All patients should receive pharmacologic prophylaxis for atrial fibrillation after cardiac surgery

In addition to the physiologic manifestations of atrial fibrillation (stroke, ventricular arrhythmia), 2 patients with postoperative arrhythmias have subjective concerns because of symptoms (palpitations), and prolonged length of stay and hospital cost are significant sources of visceral morbidity to both patients and their physicians. Efforts to terminate this arrhythmia after its initiation are fraught with problems ranging from ineffectiveness to toxicity. Fortunately, a variety of pharmacologic strategies are now available to prevent atrial fibrillation after cardiac surgery. At a minimum, low-dose postoperative β-adrenergic blockade is valuable for patients who receive these medications preoperatively and may be beneficial in all patients. Moreover, emerging data suggest that prophylaxis with antiarrhythmic compounds can significantly decrease the incidence of atrial fibrillation, length of hospital stay, and cost. Future trials will be focused on evaluating the risks and benefits of the newer prophylactic therapies and defining which subpopulations benefit most from such therapy.

Experimental evidence for proarrhythmic mechanisms of antiarrhythmic drugs.

The major limitation to antiarrhythmic drug therapy is the risk of arrhythmia promotion, or 'proarrhythmia.' This complication may be lethal, and greatly restricts the value of antiarrhythmic agents, particularly for arrhythmias without an intrinsic mortality risk, such as atrial fibrillation. In order for improved antiarrhythmic drug therapy to be developed, it is essential to understand the fundamental mechanisms that cause proarrhythmic reactions to antiarrhythmic drugs. The present article reviews the experimental evidence that has been obtained regarding the mechanisms of proarrhythmia. The evidence available provides important insights, and points to potential strategies for developing newer and safer antiarrhythmic compounds.

P-570 - Effects of AH-1058, a potent antiarrhythmic compound, on the membrane currents of guinea-pig cardiomyocytes

P-570 - Effects of AH-1058, a potent antiarrhythmic compound, on the membrane currents of guinea-pig cardiomyocytes

Hemodynamic Effects of Antiarrhythmic Compounds: Intrinsic Effects and Autonomic Modulation

Besides their proarrhythmic side-effects, most antiarrhythmic drugs exert varying degrees of depressant action on hemodynamics, which may limit their utility, especially in patients with compromised left ventricular function. Antiarrhythmic drugs have not only myocardial inotropic effects but also act on the coronary and peripheral circulation and the heart rate. Thus, sophisticated and appropriate experimental conditions are necessary to define the effect of their direct negative inotropic actions versus their circulatory effects and the impact of drug-induced autonomic modulation. This study describes an extended comparison of amiodarone, d-sotalol, d,l-sotalol, and dofetilide as class III antiarrhythmic drugs with the actions of several class I antiarrhythmic drugs in an open-chest model. The experimental model permits not only measurements in the intact circulation but also measurements of isovolumic indexes of contractility, which are independent of drug-induced changes in ventricular preload and afterload. Furthermore, after autonomic blockade, hemodynamic effects can be measured independently of modulatory adrenergic effects in such a model. d-Sotalol and amiodarone had cardiodepressant effects only at doses significantly higher than the highest doses used clinically. Dofetilide did not have a negative inotropic effect at doses up to 40 ng/kg. However, these results might be modified in experimental models with severely compromised left ventricular function, as was shown for class I antiarrhythmic drugs and for d,l- and d-sotalol. The sensitivity to a drug’s negative inotropic action is markedly increased in functionally impaired myocardium. Furthermore, in a model of postischemic myocardial dysfunction, the depressant effect of d-sotalol could largely be avoided by previous autonomic blockade, indicating the importance of the residual β-blocking potency of d-sotalol in the doses used in our experiments. Thus, in clinically relevant doses amiodarone, d-sotalol, and dofetilide were found to be devoid of negative inotropic actions in the setting of normal left ventricular myocardium. In failing hearts, such effects become more readily evident than they do in normal hearts after high doses of amiodarone and d-sotalol. From β-blocking experiments in hearts with left ventricular dysfunction, it could be inferred that residual β-blocking and other negative inotropic mechanisms may produce a net negative inotropic action, thus masking the minor positive class III effects postulated from in vitro experiments. These observations may have significant clinical implications, because they suggest that the intrinsic myocardial effects of antiarrhythmic drugs may be modified by autonomic effects, the status of ventricular function, and changes in preload and afterload.

The protective effect of class III antiarrhythmic agents against calcium overload in cultured myocytes

Calcium ions have been implicated in the mechanisms of ventricular arrhythmias. Impairment of intercellular coupling by calcium overload is considered to facilitate ventricular fibrillation (VF) and to sup-press its self termination. According to our hypothesis, any compound that decreases intracellular calcium concentration [Ca 2+] i during VF can serve as defibrillating drug. In this study, we examined the effect of d-sotalol and tedisamil on calcium overload in cultured, spontaneously beating rat cardiomyocytes. The changes of [Ca 2+] i were measured by indo-1 method and the intercellular synchronization by image analysis. The results showed that increase in [Ca 2+] o from 1.9 mM to 3.9 mM increased [Ca 2+] i from 100 nM to 320 nM and transformed the synchronized cell movement to an asynchronous one. Administration of 5 × 10 −6 M d-sotalol or 10 −6 M tedisamil, decreased the [Ca 2+] i to its basic level and restored the synchronized activity. In summary: Our results showed that increase in [Ca 2+] i known to caused inhibition of intercellular coupling, that could lead to arrhythmia and fibrillation while d-sotalol or tedisamil prevented this effect. These results support our hypothesis, that class III antiarrhythmic compounds with positive inotropic effect, increase intercellular synchronization, by decreasing free [Ca 2+] i, most probably by increasing the Ca 2+ uptake by the sarcoplasmic reticulum, and therefore act as a defibrillating compound.

Amiodarone: the expanding antiarrhythmic role and how to follow a patient on chronic therapy.

Amiodarone was introduced as an antiarrhythmic compound in the early 1970s and was approved in the U.S. for the treatment of refractory ventricular arrhythmias in late 1984. Since that time the drug has become the most widely studied antiarrhythmic compound with expanding potential indications, including maintaining stability of sinus rhythm, secondary prevention in the survivors of myocardial infarction, and prolongation of survival in certain subsets of patients with congestive heart failure. Intravenous amiodarone was introduced in the U.S. in 1995 for the control of recurrent destabilizing ventricular tachycardia or ventricular fibrillation resistant to conventional therapy. The level of comfort in its use has risen considerably in the recent past. This has stemmed from the reasonably decisive evidence that class I agents increase mortality in patients with structural heart disease. In contrast, amiodarone either reduces mortality or its effect is neutral; this is consistent with its low to negligible proarrhythmic actions. The drug does not aggravate heart failure and it may even increase left ventricular ejection fraction and improve exercise capacity. Above all, it is becoming increasingly evident from wider experience and from controlled clinical trials that the side-effect profile of the drug is not as compelling an issue as it appeared to be when first used in much higher doses. Therefore, the overall objective of amiodarone therapy is to use the lowest dose that produces a defined therapeutic end point without causing serious side effects. Careful clinical surveillance in conjunction with monitoring of certain laboratory parameters and indices of efficacy at regular intervals permits the drug to be used effectively in a large number of patients who fail to respond to, or are intolerant of other antiarrhythmic compounds. Many experienced clinicians have begun to consider the use of amiodarone as first-line therapy in certain disorders of rhythm, especially in patients with severely compromised ventricular function.

Application of a Continuous-Time Markov Chain to a Preclinical Study

A continuous-time Markov model is used to analyze electrocardiogram data obtained from a preclinical study in rabbits of five antiarrhythmic compounds. The preclinical protocol and data are introdu...

INDIRECT PARASYMPATHOMIMETIC ACTIVITY OF THE CLASS III ANTIARRHYTHMIC SUBSTANCE D/ L-SOTALOL IN VITRO: REVERSIBLE INHIBITION OF CHOLINESTERASE ISOENZYMES FROM BLOOD AND THE HUMAN CENTRAL NERVOUS SYSTEM

Inhibitory effects of the class III antiarrhythmic compound D/ L-sotalol on acetylcholinesterase (AChE; EC 3.1.1.7) isoenzymes of both erythrocytes and the human caudate nucleus and on serum cholinesterase (ChE; EC 3.1.1.8) were studied in vitrousing a spectrophotometric kinetic assay with acetylthiocholine (ASCh) as substrate. Sotalol concentrations in the assays varied from 0.32 to 3.2m M. All isoenzymes studied were inhibited by D/ L-sotalol in a reversible and concentration-dependent manner. Double reciprocal plots of the reaction velocity against varying ASCh concentrations revealed that D/ L-sotalol reduced substrate affinity (apparent Michaelis constant, KM, increased) of serum ChE, but did not change the enzyme's maximal rate of ASCh hydrolysis (V max). Thus, D/ L-sotalol inhibition of serum ChE was of the competitive type (rate constant for reversible competitive inhibition: K i=0.51m M). In contrast, D/ Lsotalol reduced the maximal reaction velocity of the AChE isoenzyme from the central nervous system (caudate nucleus), but had no influence on substrate affinity of the enzyme (K Mwith ASCh unchanged) indicating purely non-competitive inhibition kinetics (rate constant of reversible non-competitive inhibition: K i′=0.44m M). D/ L-sotalol inhibition of erythrocyte AChE was of mixed competitive/non-competitive type (K i=0.31m M, K i′=0.49m M). Non-competitive D/ L-sotalol inhibition of caudate nucleus AChE and the non-competitive component of erythrocyte AChE inhibition cannot be overcome by increased concentrations of the cholinergic transmitter acetylcholine (ACh). Peak D/ L-sotalol plasma levels as described in the literature for both humans (15μ M) and experimental animals (dogs: 18μ M; rats: 260μ M) as well as maximal myocardial concentrations of the substance (dogs: 46μ M; rats: 478μ M) are in the range of about 2% to 100% of the sotalol inhibition rate constants determined in the present paper for cholinesterase isoenzymes in vitro. Thus, D/ L-sotalol inhibition of ACh hydrolysis in vivomay contribute to both the well known antiarrhythmic potential and proarrhythmic side effects of the compound.

Antiarrhythmic Actions of Amiodarone: A Profile of a Paradoxical Agent

Amiodarone, a complex compound with variegated electropharmacologic and pharmacokinetic properties and an equally complex side-effect profile, continues to have a critical role in the control of ventricular and supraventricular tachyarrhythmias as the use of class I agents has declined. Such is also the case with sotalol. Unlike other so-called class III agents, amiodarone non-competitively blocks sympathetic stimulation, and its effects on repolarization are not associated with reverse use dependency. Rarely does it produce torsades de pointes despite its propensity to induce significant bradycardia and marked prolongation of the QT interval. During long-term therapy with the drug, there is no impairment of ventricular function; in fact, there are significant increases in the left ventricular ejection fraction during protracted amiodarone therapy in patients with heart failure. Long-term amiodarone administration consistently demonstrates marked efficacy in a wide spectrum of arrhythmias. The major limitation of amiodarone during long-term therapy is its unusual side-effect profile, although the increasing trend for low-dose drug therapy has demonstrated a major decline in the overall incidence of serious adverse reactions. Amiodarone is effective in controlling symptomatic ventricular tachycardia and fibrillation (VT/VF) in >60–70% of patients when conventional agents (especially class I) are ineffective or not well tolerated. The efficacy of amiodarone compared with that of an implantable cardioverter-defibrillator in patients with VT/VF and in survivors of cardiac arrest remains uncertain when total mortality is used as the primary endpoint of comparison. Amiodarone suppresses ventricular ectopy and markedly suppresses nonsustained VT. It prevents inducible VT/VF in a small number of patients, but slows VT rate in a larger number. The role of the drug in prolonging survival in the postmyocardial infarction patient is unclear, although preliminary data from blinded studies suggest that the drug decreases arrhythmia-related mortality. Similarly, in heart failure, amiodarone has the potential to reduce total mortality but appears to be selectively effective in nonischemic rather than in ischemic cardiomyopathy. Intravenous amiodarone was recently introduced in the United States for the control of recurrent destabilizing VT or VF resistant to conventional therapy. There is also evolving data indicating that the drug might be the most potent agent in maintaining sinus rhythm in patients with atrial fibrillation or flutter converted chemically or electrically to sinus rhythm. However, blinded controlled comparative studies involving sotalol, quinidine, or pure class III drugs have not been carried out. The available data nevertheless suggest that, barring its side-effect profile, amiodarone is a desirable prototype of a broad-spectrum antifibrillatory and antiarrhythmic compound. (Am J Cardiol 1996;78(suppl 4A):41–53)

Separation of the components of the delayed rectifier potassium current using selective blockers of IKr and IKs in guinea-pig isolated ventricular myocytes.

Delayed rectifier potassium current (IK) was investigated in guinea-pig isolated ventricular myocytes under voltage-clamp conditions ('switched' single electrode clamp), using selective blockers and/or different activation protocols to separate its rapid (IKr) and slow (IKs) components. The class III antiarrhythmic compound E4031 (5 microM) was used to block IKr and the anaesthetic drugs propofol (100 microM) or thiopentone (100 microM) to block IKs. In all experiments L-type calcium currents were blocked with nifedipine (2 microM). Complementary effects of E4031 and the anaesthetic drugs on the components of IK were observed. The E4031-sensitive current (IKr) resembled the current remaining in the presence of the anaesthetics and, likewise, the anaesthetic-sensitive current (IKs) resembled the current remaining in the presence of E4031. Under the conditions of these experiments, the relative contribution of the two components to total IK tail current was found to be approximately equal after a 400 ms depolarization to +40 mV. For example, IKr was 58 +/- 10% of total IK tail current when measured as the E4031-sensitive current, 41 +/- 6% as the propofol-insensitive current and 43 +/- 7% as the thiopentone-insensitive current. In the presence of both E4031 and propofol or thiopentone the IK tail current deactivating at -40 mV was completely eliminated, leaving a residual current during the pulse which reversed at -46 +/- 1 mV. To avoid complication of the 'envelope of tails' test with this residual current, the tail:pulse ratio was calculated for the anaesthetic-sensitive component and this was constant, consistent with block of a single component of IK. Forskolin (1 microM) enhanced the current most consistent with IKs. Propofol (300 microM) caused a 64 +/- 3% increase in action potential duration in the presence of both E4031 (5 microM) and nifedipine (2 microM), consistent with an important role for IKs in the repolarization of the action potential in the guinea-pig heart. The observations therefore provide further support for separate components of IK with different characteristics in the guinea-pig heart; it appears that E4031 and propofol or thiopentone are useful complementary tools for their separation.

EFFECTS OF BISARAMIL ON CORONARY-OCCLUSION-REPERFUSION INJURY AND FREE-RADICAL-INDUCED REACTIONS

The aim of this study was to determine whether bisaramil—an antiarrhythmic compound under clinical investigation—influences the reperfusion–induced arrhythmias and biochemical parameters characterizing occlusion-reperfusion-induced free-radical reactions. The left descending coronary artery (LAD) was occluded for 60min in anaesthetized dogs followed by one hour of reperfusion. Blood samples were taken at different times of the occlusion and reperfusion for the determination of plasma concentration of malondialdehyde (MDA), reduced (GSH) and oxidized glutathione (GSSG); furthermore of the activity of catalase and superoxide dismutase (SOD). Free-radical generating capacity of polymorph neutrophil granulocytes (PMN) was also measured. At the end of the experiments heart tissue samples were excised from the injured areas and from the intact part of the left ventricular muscle. In tissue samples the concentrations of MDA and GSH and the activity of SOD were determined. Bisaramil was given as an i.v. bolus injection at a dose of 2mgkg −1several minutes prior to the end of LAD-occlusion; then the administration was repeated in the 30th minute of reperfusion. In the control group (10 dogs) ventricular fibrillation (VF) occurred in seven cases which resulted in death in three. In the bisaramil-treated group, however, VF was seen in three cases and no death was recorded. Bisaramil inhibited the elevation of the plasma concentration of MDA and GSSG during the reperfusion and abolished the decrease in the plasma concentration of GSH during the occlusion and reperfusion. The activity of SOD and catalase in plasma was much better preserved in the bisaramil-treated group then in the controls. Bisaramil significantly inhibited the increase of the superoxide-radical generating capacity of PMNs during the reperfusion. The data obtained from myocardial tissue samples supported the cardioprotective effect of bisaramil. The biochemical investigation of ischemic-reperfused myocardium showed that bisaramil promoted preservation of SOD-activity and of tissue glutathione. Results of this study clearly showed that bisaramil has a significant effect on ischemia-reperfusion injury. Besides its inhibitory effects on ischaemia-reperfusion induced arrhythmias it has a special benefit in influencing free-radical mediated damage leading to better preservation of membranes and to limitations of irreversible cell injuries.

Efficacy and safety of d-Sotalol, a pure class III antiarrhythmic compound, in patients with symptomatic complex ventricular ectopy: Hohnloser SH, Meinertz T, Stubbs P, et al. Circulation. 1995; 92:1517–1525

Efficacy and safety of d-Sotalol, a pure class III antiarrhythmic compound, in patients with symptomatic complex ventricular ectopy: Hohnloser SH, Meinertz T, Stubbs P, et al. Circulation. 1995; 92:1517–1525

Almokalant—A Selective Class III Antiarrhythmic Compound

Almokalant—A Selective Class III Antiarrhythmic Compound