Current Medicinal Chemistry - Volume 18, Issue 24, 2011

Development of more and more effective antiarrhythmic agents has been in the focus of interest of drug research during the last four decades. The ideal omnipotent compound, however, has not been shown up so far. The currently applied antiarrhythmic strategies largely follow the classic scheme of Vaughan Williams [1], which has been modified several times since its first publication [2, 3]. According to this classification, class 1 drugs suppress action potential upstroke and intraventricular conduction velocity due to inhibition of fast sodium channels in a use-dependent manner. Class 2 agents block beta-adrenergic receptors, resulting in reduction of intracellular cAMP level, and consequently, the activity of several cAMP-activated ion channels. Class 3 compounds prolong action potential duration, and consequently, the refractory period, decreasing this way the probability of formation of re-entrant circuits. Class 4 drugs are calcium channel antagonists reducing Ca2+ entry into cardiac cells, which, in turn, improves impulse propagation and helps to prevent the development of triggered activity in Ca2+- loaded myocardium. Each of these antiarrhythmic mechanisms, however, may also carry serious proarrhythmic risks [4]. For instance, prolongation of action potentials due to class 3 antiarrhythmic action increases Ca2+ content of cardiac cells and facilitates reactivation of ICa. These mechanisms are responsible for generation of late and early afterdepolarizations, respectively [5, 6]. Class 1 agents, especially those having slow turn-off kinetics, likely impair conduction of normal impulses as well [7], which is also believed to be proarrhythmic [4]. Similarly, inhibition of ICa - either as a consequence of a beta-adrenergic blockade, or directly, due to application of Ca2+ entry blockers - may slow conduction in nodal tissues. Most of these theoretical considerations are unfortunately supported by results of clinical trials, where many antiarrhythmics have been shown to increase mortality. The increased mortality observed in the CAST study [8] with 1/C agents may primarily be associated with proarrhythmic effects of these drugs, although their negative inotropic action leading to heart failure may also have been involved. The increased mortality observed in d-sotalol treated patients of the SWORD study [9] was clearly due to the reverse rate-dependent torsadogenic action of the compound. It could, therefore, be concluded that, in spite of the relative efficacy of many class 3 drugs including dofetilide [10], a new group of selective class 3 agents, devoid of reverse rate-dependent action, should be developed [11]. It is shown by the present work of Banyasz et al. why this concept is not feasible, i.e. application of selective class 3 drugs is not necessarily the optimal treatment of cardiac arrhythmias. In contrast, if suppression of repolarization may be torsadogenic, then assistance of repolarization by enhancement of an outward current, such as IKr, may also exert antiarrhythmic actions. This heretical doctrine is discussed by Szabo et al. in their review article. The controversial experimental and disappointing clinical observations inspired the development of new antiarrhythmic strategies. Accordingly, new potential targets for antiarrhytmic drug therapy, such as manipulation of the endogeneous adenosinergic mechanisms, the Ca2+-activated as well as the ATP-sensitive potassium channels, or suppression of the If pacemaker current, have been emerged. An example for each of these novel approaches are presented in this Special Issue. Since ventricular fibrillation is acutely lethal, most of our efforts to suppress cardiac arrhythmias have been directed to ventricular myocardium. Atrial fibrillation may also be lethal - although at a much longer time scale. However, the quality of life with perpetual of frequently manifesting atrial fibrillation is strongly compromised. The state of art summary of the recent progress in treatment of atrial fibrillation is provided by the excellent paper of Jost et al. If considering the possibilities offered by the somewhat farther future, the precise and detailed understanding of regulation of cardiac ion currents, including the contribution of various signal transduction cascades in this control, may be crucial. Some of these important pathways of regulation (e.g. the adrenergic and purinergic control of the heart) have long been studied; however, recent results may modify the perspectives of their authentic manipulation. The research history of calmodulin kinase - one of the most important mechanism responsible for Ca2plus;- dependent regulation of ion channels in the heart - is not too long, but extremely promising. Cardiac arrhythmias are often combined with electrical remodeling - electrical changes caused by long lasting pathological events. This may alter the density, as well as the kinetic properties of cardiac ion channels, which, in turn, may be important from the point of view of the antiarrhythmic strategy to be applied. Mechanisms involved in long term regulation of L-type calcium channels seen in the presence of calcium channel blockers are highlighted by the study of Magyar et al.....

Class 3 antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD), i.e. changes in APD are greater at longer than at shorter cycle lengths. In spite of the several theories developed to explain this reverse rate-dependency, its mechanism has been clarified only recently. The aim of the present study is to elucidate the mechanisms responsible for reverse ratedependency in mammalian ventricular myocardium. Action potentials were recorded using conventional sharp microelectrodes from human, canine, rabbit, guinea pig, and rat ventricular myocardium in a rate-dependent manner. Rate-dependent drug-effects of various origin were studied using agents known to lengthen or shorten action potentials allowing thus to determine the drug-induced changes in APD as a function of the cycle length. Both drug-induced lengthening and shortening of action potentials displayed reverse ratedependency in human, canine, and guinea pig preparations, but not in rabbit and rat myocardium. Similar results were obtained when repolarization was modified by injection of inward or outward current pulses in isolated canine cardiomyocytes. In contrast to reverse ratedependence, drug-induced changes in APD well correlated with baseline APD values (i.e. that measured before the superfusion of drug or injection of current) in all of the preparations studied. Since the net membrane current (Inet), determined from the action potential waveform at the middle of the plateau, was inversely proportional to APD, and consequently to cycle length, it is concluded that that reverse rate-dependency may simply reflect the inverse relationship linking Inet to APD. In summary, reverse rate-dependency is an intrinsic property of drug action in the hearts of species showing positive APD - cycle length relationship, including humans. This implies that development of a pure K+ channel blocking agent without reverse rate-dependent effects is not likely to be successful.

The delayed rectifier potassium current (IK) 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 (IKs) and a rapid (IKr) 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 ICa, IKr, IKs, and Ito. 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 IKr activation is not questioned.

Normal heart function and repolarization of the cardiac action potential (AP) is to a high extent subjective to synchronized activity of sarcolemmal K+ channels, expressed in both ventricular and atrial myocardium, largely contributing to regulation of the resting potential, the pacemaker activity, and the shape and duration of the AP. Clinical observations and experimental studies in cardiomyocytes and multicellular preparations provided firm evidence for the sensitivity of some major outward K+ currents and the corresponding ion channels to shifts in intracellular Ca2+ concentration ([Ca2+]i). Direct regulation via interaction between [Ca2+]i and the channel protein or indirect modulation via Ca2+ signaling pathways of these currents have strong implications to mechanical and electrical performance of the heart, and its physiological adaptation to altered load. It may also lead to severe cardiac dysfunction, if [Ca2+]i handling is disturbed in a variety of pathological conditions. In this review we attempt to summarize the present state of the topic on two ubiquitous repolarizing K+ currents (Ito1 and IK1) with documented Ca2+-sensitivity and critical significance in cellular antiarrhythmic defense, to highlight fields where clue data are missing, and discuss the apparently unsolved “mystery” of the cardiac small conductance Ca2+-activated K+ (SK) channels. We have collected the available information on the known novel, although usually still not enough selective inhibitors and activators of these currents justifying the need for more selective ones. Finally, we emphasize a few related therapeutical perspectives to be considered for future experimental research and particularly in pharmaceutical development.

Cardiac atrial and ventricular arrhythmias are major causes of mortality and morbidity. Ischemic heart disease is the most common cause underlying 1) the development of ventricular fibrillation that results in sudden cardiac death and 2) atrial fibrillation that can lead to heart failure and stroke. Current pharmacological agents for the treatment of ventricular and atrial arrhythmias exhibit limited effectiveness and many of these agents can cause serious adverse effects - including the provocation of lethal ventricular arrhythmias. Sarcolemmal ATP-sensitive potassium channels (sarcKATP) couple cellular metabolism to membrane excitability in a wide range of tissues. In the heart, sarcKATP are activated during metabolic stress including myocardial ischemia, and both the opening of sarcKATP and mitochondrial KATP channels protect the ischemic myocardium via distinct mechanisms. Myocardial ischemia leads to a series of events that promote the generation of arrhythmia substrate eventually resulting in the development of life-threatening arrhythmias. In this review, the possible mechanisms of the anti- and proarrhythmic effects of sarcKATP modulation as well as the influence of pharmacological KATP modulators are discussed. It is concluded that in spite of the significant advances made in this field, the possible cardiovascular therapeutic utility of current sarcKATP channel modulators is still hampered by the lack of chamber-specific selectivity. However, recent insights into the chamber-specific differences in the molecular composition of sarcKATP in addition to already existing cardioselective sarcKATP channel modulators with sarcKATP isoform selectivity holds the promise for the future development of pharmacological strategies specific for a variety of atrial and ventricular arrhythmias.

The pacemaker channel isoforms are encoded by the hyperpolarization-activated and cyclic nucleotide-gated (HCN) gene family and are responsible for diverse cellular functions including regulation of spontaneous activity in sino-atrial node cells and control of excitability in different types of neurons. Four channel isoforms exist (HCN1-HCN4). The hyperpolarization-activated cardiac pacemaker current (If) has an important role in the generation of the diastolic depolarization in the sino-atrial node, while its neuronal equivalent (Ih) is an important contributor to determination of resting membrane potential, and plays an important role in neuronal functions such as synaptic transmission, motor learning and generation of thalamic rhythms. Ivabradine is a novel, heart rate-lowering drug which inhibits the pacemaker (If) current in the heart with high selectivity and with minimal effect on haemodynamic parameters. Ivabradine is beneficial in patients with chronic stable angina pectoris equally to beta receptor blocker and calcium channel antagonist drugs. There is increasing interest to apply this drug in other fields of cardiology such as heart failure, myocardial infarction, cardiac arrhyhtmias. Heart rate reduction might improve clinical outcomes in heart failure. HCN upregulation presumably contributes to increased (If) and may play a role in ventricular and atrial arrhythmogenesis in heart failure. In the nervous system the HCN channels received attention in the research areas of neuropathic pain, epilepsy and understanding the mechanism of action of volatile anaesthetics. This article delineates that the pharmacological modulation of cardiac and neuronal HCN channels can serve current or future drug therapy and introduces some recently investigated HCN channel inhibitor compounds being potential candidates for development.

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. It can occur at any age, however, it becomes extremely common in the elderly, with a prevalence approaching more than 20% in patients older than 85 years. AF is associated with a wide range of cardiac and extra-cardiac complications and thereby contributes significantly to morbidity and mortality. Present therapeutic approaches to AF have major limitations, which have inspired substantial efforts to improve our understanding of the mechanisms underlying AF, with the premise that improved knowledge will lead to innovative and improved therapeutic approaches. Our understanding of AF pathophysiology has advanced significantly over the past 10 to 15 years through an increased awareness of the role of “atrial remodeling”. Any persistent change in atrial structure or function constitutes atrial remodeling. Both rapid ectopic firing and reentry can maintain AF. Atrial remodeling has the potential to increase the likelihood of ectopic or reentrant activity through a multitude of potential mechanisms. The present paper reviews the main novel results on atrial tachycardia-induced electrical, structural and contractile remodeling focusing on the underlying pathophysiological and molecular basis of their occurrence. Special attention is paid to novel strategies and targets with therapeutic significance for atrial fibrillation.

Methylxanthines, such as theophylline, have been used to treat cardiorespiratory disorders, whereas caffeine is the most widely consumed psychoactive agent in various soft drinks. Because of the worldwide use of these drugs and the recently synthesized xanthine derivatives, an intensive research on the cardiac actions of these substances is under progress. This review focuses on the molecular mechanisms involved in the actions of xanthine derivatives with special reference to their adenosine receptor antagonistic properties. The main basic and human studies on the action of xanthines on impulse initiation and conduction, as well as the electrophysiological and mechanical activity of the working myocardium will be overviewed. The potential beneficial and harmful actions of the methylxanthines will be discussed in light of the recent experimental and clinical findings. The pharmacological features and clinical observations with adenosine receptor subtype-specific xanthine antagonists are also the subject of this paper. Based on the adenosine receptor-antagonistic activity of these compounds, it can be raised that xanthine derivatives might inhibit the cardioprotective action of endogenous adenosine on various subtypes (A1, A2A, A2B and A3) of adenosine receptors. Adenosine is an important endogenous substance with crucial role in the regulation of cardiac function under physiological and pathological conditions (preconditioning, postconditioning, ischemia/ reperfusion injury). Recent clinical studies show that acute administration of caffeine or theophylline can inhibit various types of preconditioning in human subjects. There are no human studies, however, for the cardiovascular actions of long-term administration of these drugs. Upregulation of adenosine receptors and increased effectiveness of adenosine receptor-related cardiovascular functions have been observed after long-lasting treatment with methylxanthines. In addition, there are data indicating that blood adenosine level increases after long-term caffeine administration. Since the salutary actions (and also the adverse reactions) of a number of xanthine derivatives are repeatedly shown, the main goal is the development of novel structures that mimic the actions of the conventional methylxanthines as lead compounds, but their adenosine receptor subtype-specificity is higher, their water solubility is optimal, and the unwanted reactions are minimized.

Therapeutic strategy for cardiac arrhythmias has undergone a remarkable change during the last decades. Currently implantable cardioverter defibrillator therapy is considered to be the most effective therapeutic method to treat malignant arrhythmias. Some even argue that there is no room for antiarrhythmic drug therapy in the age of implantable cardioverter defibrillators. However, in clinical practice, antiarrhythmic drug therapies are frequently needed, because implantable cardioverter defibrillators are not effective in certain types of arrhythmias (i.e. premature ventricular beats or atrial fibrillation). Furthermore, given the staggering cost of device therapy, it is economically imperative to develop alternative effective treatments. Cardiac ion channels are the target of a number of current treatment strategies, but therapies based on ion channel blockers only resulted in moderate success. Furthermore, these drugs are associated with an increased risk of proarrhythmia, systemic toxicity, and increased defibrillation threshold. In many cases, certain ion channel blockers were found to increase mortality. Other drug classes such as β blockers, angiotensin-converting enzyme inhibitors, aldosterone antagonists, and statins appear to have proven efficacy for reducing cardiac mortality. These facts forced researchers to shift the focus of their research to molecular targets that act upstream of ion channels. One of these potential targets is calcium/calmodulin-dependent kinase II (CaMKII). Several lines of evidence converge to suggest that CaMKII inhibition may provide an effective treatment strategy for heart diseases. (1) Recent studies have elucidated that CaMKII plays a key role in modulating cardiac function and regulating hypertrophy development. (2) CaMKII activity has been found elevated in the failing hearts from human patients and animal models. (3) Inhibition of CaMKII activity has been shown to mitigate hypertrophy, prevent functional remodeling and reduce arrhythmogenic activity. In this review, we will discuss the structural and functional properties of CaMKII, the modes of its activation and the functional consequences of CaMKII activity on ion channels.

Calcium ions are crucial elements of excitation-contraction coupling in cardiac myocytes. The intracellular Ca2+ concentration changes continously during the cardiac cycle, but the Ca2+ entering to the cell serves as an intracellular second messenger, as well. The Ca2+ as a second messenger influences the activity of many intracellular signalling pathways and regulates gene expression. In cardiac myocytes the major pathway for Ca2+ entry into cells is L-type calcium channel (LTCC). The precise control of LTCC function is essential for maintaining the calcium homeostasis of cardiac myocytes. Dysregulation of LTCC may result in different diseases like cardiac hypertrophy, arrhytmias, heart failure. The physiological and pathological structural changes in the heart are induced in part by small G proteins. These proteins are involved in wide spectrum of cell biological functions including protein transport, regulation of cell proliferation, migration, apoptosis, and cytoskeletal rearrangement. Understanding the crosstalk between small G proteins and LTCC may help to understand the pathomechanism of different cardiac diseases and to develop a new generation of genetically-encoded Ca2+ channel inhibitors.

Recent large clinical trials found an association between the antidiabetic drug rosiglitazone therapy and increased risk of cardiovascular adverse events. The aim of this report is to elucidate the cardiac electrophysiological properties of rosiglitazone (R) on isolated rat and murine ventricular papillary muscle cells and canine ventricular myocytes using conventional microelectrode, whole cell voltage clamp, and action potential (AP) voltage clamp techniques. In histidine-decarboxylase knockout mice as well as in their wild types R (1-30 μM) shortened AP duration at 90%% level of repolarization (APD90) and increased the AP amplitude (APA) in a concentration-dependent manner. In rat ventricular papillary muscle cells R (1-30 μM) caused a significant reduction of APA and maximum velocity of depolarization (Vmax) which was accompanied by lengthening of APD90. In single canine ventricular myocytes at concentrations ≥10 μM R decreased the amplitude of phase-1 repolarization, the plateau potential and reduced Vmax. R suppressed several ion currents in a concentration-dependent manner under voltage clamp conditions. The EC50 value for this inhibition was 25.2±2.7 μM for the transient outward K+ current (Ito), 72.3±9.3 μM for the rapid delayed rectifier K+ current (IKr), and 82.5±9.4 μM for the L-type Ca2+ current (ICa) with Hill coefficients close to unity. The inward rectifier K+ current (IK1) was not affected by R up to concentrations of 100 μM. Suppression of Ito, IKr, and ICa has been confirmed under action potential voltage clamp conditions as well. The observed alterations in the AP morphology and densities of ion currents may predict serious proarrhythmic risk in case of intoxication with R as a consequence of overdose or decreased elimination of the drug, particularly in patients having multiple cardiovascular risk factors, such as elderly diabetic patients.

Receptor-mediated changes in intracellular cyclic AMP concentration play critical role in the autonomic control of the heart, including regulation of a variety of ion channels via mechanisms involving protein kinase A, EPAC, or direct actions on cyclic nucleotide gated ion channels. In case of any ion channel, the actual signal transduction cascade can be identified by using properly modified cAMP derivatives with altered binding and activating properties. In this study we focus to structural modifications of cAMP resulting in specific activator and blocking effects on PKA or EPAC. Involvement of the cAMP-dependent signal transduction pathway in controlling rapid delayed rectifier K+ current was studied in canine ventricular myocytes using these specific cAMP analogues. Adrenergic stimulation increased the density of IKr in canine ventricular cells, which effect was mediated by a PKA-dependent but EPAC-independent pathway. It was also shown that intracellular application of large concentrations of cAMP failed to fully activate PKA comparing to the effect of isoproterenol, forskolin, or PDE-resistant cAMP derivatives. This difference was fully abolished following inhibition of phosphodiesterase by IBMX. These results are in line with the concept of compartmentalized release, action, and degradation of cAMP within signalosomes.

Action potential voltage-clamp (APVC) is a technique to visualize the profile of various currents during the cardiac action potential. This review summarizes potential applications and limitations of APVC, the properties of the most important ion currents in nodal, atrial, and ventricular cardiomyocytes. Accordingly, the profiles (“fingerprints”) of the major ion currents in canine ventricular myocytes, i.e. in cells of a species having action potential morphology and set of underlying ion currents very similar to those found in the human heart, are discussed in details. The degree of selectivity of various compounds, which is known to be a critical property of drugs used in APVC experiments, is overviewed. Thus the specificity of agents known to block sodium (tetrodotoxin, saxitoxin), potassium (chromanol 293B, HMR 1556, E-4031, dofetilide, sotalol, 4-aminopyridine, BaCl2), calcium (nifedipine, nisolpidine, nicardipine, diltiazem, verapamil, gallopamil), and chloride (anthracene-9-carboxylic acid, DIDS) channels, the inhibitor of the sodium-calcium exchanger (SEA0400), and the activator of sodium current (veratridine) are accordingly discussed. Based on a theory explaining how calcium current inhibitors block calcium channels, the structural comparison of the studied substances usually confirmed the results of the literature. Using these predictions, a hypothetical super-selective calcium channel inhibitor structure was designed. APVC is a valuable tool not only for studying the selectivity of the known ion channel blockers, but is also suitable for safety studies to exclude cardiac ion channel actions of any agent under development.