Multiple Ionic Currents Research Articles

Cellular and Molecular Mechanisms of Arrhythmia by Oxidative Stress.

Current therapies for arrhythmia using ion channel blockade, catheter ablation, or an implantable cardioverter defibrillator have limitations, and it is important to search for new antiarrhythmic therapeutic targets. Both atrial fibrillation and heart failure, a condition with increased arrhythmic risk, are associated with excess amount of reactive oxygen species (ROS). There are several possible ways for ROS to induce arrhythmia. ROS can cause focal activity and reentry. ROS alter multiple cardiac ionic currents. ROS promote cardiac fibrosis and impair gap junction function, resulting in reduced myocyte coupling and facilitation of reentry. In order to design effective antioxidant drugs for treatment of arrhythmia, it is essential to explore the molecular mechanisms by which ROS exert these arrhythmic effects. Activation of Ca2+/CaM-dependent kinase II, c-Src tyrosine kinase, protein kinase C, and abnormal splicing of cardiac sodium channels are among the recently discovered molecular mechanisms of ROS-induced arrhythmia.

Calibration of an in‐silico Human Ventricular Action Potential Model to Detect Proarrhythmic Liabilities

In‐silico models of human ventricular action potentials (APs) are useful for defining the roles of specific ionic currents on cardiac repolarization and integrating drug effects on multiple cardiac ionic currents. To provide utility in defining proarrhythmic risk, these models need to be adequately benchmarked regarding their ability to generate cellular proarrhythmia. The present studies calibrated the proarrhythmic liabilities of blocking single and multiple ionic currents using ventricular APs from the O'Hara‐Rudy (ORd) model based on delayed repolarization and early afterdepolarization (EAD) activity.An endocardial cell model paced at a cycle length (CL) of 4 sec was used to reconstruct AP changes; the maximal conductance of IKr (hERG current), along with IKs, ICaL, INaL, and Na/K pump current were reduced (both individually and in concert with IKr).Decreasing IKr conductance caused AP prolongation and typically required 150‐250+ beats to reach steady‐state responses when no EADs were present. EADs were first observed when IKr was reduced by 85%; additional IKr block yielded APs with patterns of 1‐6+ EADs. When concurrently blocking IKr, EADs were less prevalent when inward currents (either ICaL or INaL) were reduced, and more prominent when outward currents (either NA/K pump or IKs) were reduced.In conclusion, in the ORd model, a) EAD activity is typically oscillatory (even after several minutes of simulated pacing), often with no stabilized, steady state rate or pattern, b) EAD activity is present only with substantial IKr block, is reduced with concomitant block of inward ICaL and INaL, and is increased by reducing IKs or Na/K pump current.This research was supported by AbbVie.

Dronedarone: Who, When, Why And How Should It Be Prescribed And Monitored?

It potentially blocks multiple ion currents, “including the rapidly activating delayed-rectifier potassium current, the slowly activating delayed-rectifier potassium current, the inward rectifier potassium current, the acetylcholine activated potassium current, peak sodium current, and L-type calcium current, and exhibits antiadrenergic effects [2].” It is also used for the maintenance of sinus rhythm and ventricular response control during atrial fibrillation episodes [2].

Interaction Between Domperidone and Ketoconazole: Toward Prediction of Consequent QTc Prolongation Using Purely In Vitro Information.

We aimed to investigate the application of combined mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation in predicting the domperidone (DOM) triggered pseudo-electrocardiogram modification in the presence of a CYP3A inhibitor, ketoconazole (KETO), using in vitro–in vivo extrapolation. In vitro metabolic and inhibitory data were incorporated into physiologically based pharmacokinetic (PBPK) models within Simcyp to simulate time course of plasma DOM and KETO concentrations when administered alone or in combination with KETO (DOM+KETO). Simulated DOM concentrations in plasma were used to predict changes in gender-specific QTcF (Fridericia correction) intervals within the Cardiac Safety Simulator platform taking into consideration DOM, KETO, and DOM+KETO triggered inhibition of multiple ionic currents in population. Combination of in vitro–in vivo extrapolation, PBPK, and systems pharmacology of electric currents in the heart was able to predict the direction and magnitude of PK and PD changes under coadministration of the two drugs although some disparities were detected.

Direct Negative Chronotropic Action of Desflurane on Sinoatrial Node Pacemaker Activity in the Guinea Pig Heart

Desflurane inhalation is associated with sympathetic activation and concomitant increase in heart rate in humans and experimental animals. There is, however, little information concerning the direct effects of desflurane on electrical activity of sinoatrial node pacemaker cells that determines the intrinsic heart rate. Whole-cell patch-clamp experiments were conducted on guinea pig sinoatrial node pacemaker cells to record spontaneous action potentials and ionic currents contributing to sinoatrial node automaticity, namely, hyperpolarization-activated cation current (If), T-type and L-type Ca currents (ICa,T and ICa,L, respectively), Na/Ca exchange current (INCX), and rapidly and slowly activating delayed rectifier K currents (IKr and IKs, respectively). Electrocardiograms were recorded from ex vivo Langendorff-perfused hearts and in vivo hearts. Desflurane at 6 and 12% decreased spontaneous firing rate of sinoatrial node action potentials by 15.9% (n = 11) and 27.6% (n = 10), respectively, which was associated with 20.4% and 42.5% reductions in diastolic depolarization rate, respectively. Desflurane inhibited If, ICa,T, ICa,L, INCX, and IKs but had little effect on IKr. The negative chronotropic action of desflurane was reasonably well reproduced in sinoatrial node computer model. Desflurane reduced the heart rate in Langendorff-perfused hearts. High concentration (12%) of desflurane inhalation was associated with transient tachycardia, which was totally abolished by pretreatment with the β-adrenergic blocker propranolol. Desflurane has a direct negative chronotropic action on sinoatrial node pacemaking activity, which is mediated by its inhibitory action on multiple ionic currents. This direct inhibitory action of desflurane on sinoatrial node automaticity seems to be counteracted by sympathetic activation associated with desflurane inhalation in vivo.

Increased Persistent Sodium Current Due to Decreased PI3K Signaling Contributes to QT Prolongation in the Diabetic Heart

Diabetes is an independent risk factor for sudden cardiac death and ventricular arrhythmia complications of acute coronary syndrome. Prolongation of the QT interval on the electrocardiogram is also a risk factor for arrhythmias and sudden death, and the increased prevalence of QT prolongation is an independent risk factor for cardiovascular death in diabetic patients. The pathophysiological mechanisms responsible for this lethal complication are poorly understood. Diabetes is associated with a reduction in phosphoinositide 3-kinase (PI3K) signaling, which regulates the action potential duration (APD) of individual myocytes and thus the QT interval by altering multiple ion currents, including the persistent sodium current INaP. Here, we report a mechanism for diabetes-induced QT prolongation that involves an increase in INaP caused by defective PI3K signaling. Cardiac myocytes of mice with type 1 or type 2 diabetes exhibited an increase in APD that was reversed by expression of constitutively active PI3K or intracellular infusion of phosphatidylinositol 3,4,5-trisphosphate (PIP3), the second messenger produced by PI3K. The diabetic myocytes also showed an increase in INaP that was reversed by activated PI3K or PIP3. The increases in APD and INaP in myocytes translated into QT interval prolongation for both types of diabetic mice. The long QT interval of type 1 diabetic hearts was shortened by insulin treatment ex vivo, and this effect was blocked by a PI3K inhibitor. Treatment of both types of diabetic mouse hearts with an INaP blocker also shortened the QT interval. These results indicate that downregulation of cardiac PI3K signaling in diabetes prolongs the QT interval at least in part by causing an increase in INaP. This mechanism may explain why the diabetic population has an increased risk of life-threatening arrhythmias.

FGF12 is a candidate Brugada syndrome locus

Less than 30% of the cases of Brugada syndrome (BrS) have an identified genetic cause. Of the known BrS-susceptibility genes, loss-of-function mutations in SCN5A or CACNA1C and their auxiliary subunits are most common. On the basis of the recent demonstration that fibroblast growth factor (FGF) homologous factors (FHFs; FGF11-FGF14) regulate cardiac Na(+) and Ca(2+) channel currents, we hypothesized that FHFs are candidate BrS loci. The goal of this study was to test whether FGF12 is a candidate BrS locus. We used quantitative polymerase chain reaction to identify the major FHF expressed in the human ventricle and then queried a phenotype-positive, genotype-negative BrS biorepository for FHF mutations associated with BrS. We queried the effects of an identified mutant with biochemical analyses combined with electrophysiological assessment. We designed a novel rat ventricular cardiomyocyte system in which we swapped the endogenous FHF with the identified mutant and defined its effects on multiple ionic currents in their native milieu and on the cardiac action potential. We identified FGF12 as the major FHF expressed in the human ventricle. In 102 individuals in the biorepository, we identified a single missense mutation in FGF12-B (Q7R-FGF12). The mutant reduced binding to the NaV1.5 C terminus, but not to junctophilin-2. In adult rat cardiac myocytes, Q7R-FGF12, but not wild-type FGF12, reduced Na(+) channel current density and availability without affecting Ca(2+) channel function. Furthermore, the mutant, but not wild-type FGF12, reduced action potential amplitude, which is consistent with a mutant-induced loss of Na(+) channel function. These multilevel investigations strongly suggest that Q7R-FGF12 is a disease-associated BrS mutation. Moreover, these data suggest for the first time that FHF effects on Na(+) and Ca(2+) channels are separable. Most significantly, this study establishes a new method to analyze effects of human arrhythmogenic mutations on cardiac ionic currents.

Stem Cell–Derived Cardiomyocytes as a Tool for Studying Proarrhythmia

Proarrhythmia is a leading cause of hospitalization for adverse drug events, and screening for proarrhythmic potential resulting from QT interval prolongation has become a major component of the development process for any new drug candidate. Conventional wisdom, now embedded in regulatory guidelines from the Food and Drug Administration and other regulatory agencies, holds that drug block of the rapid component of the cardiac delayed-rectifier potassium current, I Kr, is the major proximate mechanism underlying prolongation of cardiac action potentials, an effect that leads to early afterdepolarizations in vitro and is manifest on the surface ECG as QT prolongation and occasionally torsades de pointes.1,2 As a result, regulatory guidance suggests an early look at I Kr blocking potency of new drug entities, even recognizing that other mechanisms, some newly described,3,4 may contribute. Article see p 1677 However, the correlation between I Kr block and QT interval prolongation is imperfect. Multiple mechanisms may underlie this “disconnect,” and a reasonable generalization is that I Kr is but one (albeit important) component of normal cardiac repolarization, and abnormalities in expression or function of other components of repolarization may, in turn, modulate the net effect of I Kr block on action potentials in cardiac myocytes and on QT interval and arrhythmia susceptibility in the whole heart. The logical extension of this line of reasoning is that screening for proarrhythmic potential should include the evaluation of not only drug effects on individual ionic currents such as I Kr contributing to repolarization but also the integrated effect of drugs on action potentials in vitro and on the QT interval in animal models and in humans. In conventional drug development programs, this is commonly accomplished by comparing the effects of a candidate drug molecule on QT intervals in human subjects with …

How do astrocytes shape synaptic transmission? Insights from electrophysiology

A major breakthrough in neuroscience has been the realization in the last decades that the dogmatic view of astroglial cells as being merely fostering and buffering elements of the nervous system is simplistic. A wealth of investigations now shows that astrocytes actually participate in the control of synaptic transmission in an active manner. This was first hinted by the intimate contacts glial processes make with neurons, particularly at the synaptic level, and evidenced using electrophysiological and calcium imaging techniques. Calcium imaging has provided critical evidence demonstrating that astrocytic regulation of synaptic efficacy is not a passive phenomenon. However, given that cellular activation is not only represented by calcium signaling, it is also crucial to assess concomitant mechanisms. We and others have used electrophysiological techniques to simultaneously record neuronal and astrocytic activity, thus enabling the study of multiple ionic currents and in depth investigation of neuro-glial dialogues. In the current review, we focus on the input such approach has provided in the understanding of astrocyte-neuron interactions underlying control of synaptic efficacy.

Apelin regulates the electrophysiological characteristics of atrial myocytes

Apelin, a potential agent for treating heart failure, has various ionic effects on ventricular myocytes. However, the effects of apelin on the atrium are not clear. The purpose of this study was to investigate the acute effects of apelin on the electrophysiological characteristics of atrial myocytes. Whole-cell patch-clamp techniques were used to investigate the action potential (AP) and ionic currents in isolated rabbit left atrial (LA) myocytes before and after the administration of apelin. Apelin reduced LA AP duration measured at 90%, 50% and 20% repolarization of the amplitude by 11 ± 3%, 24 ± 5%, 30 ± 7% at 1 nM (n = 11), and by 14 ± 4%, 36 ± 6% and 45 ± 5% at 10 nM (n = 11), but not at 0·1 nM. Apeline (0·1, 1, 10 nM) did not change the amplitude, or resting membrane potential in LA myocytes. Apelin (1 nM) increased sodium currents, ultra-rapid potassium currents and the reverse mode of sodium-calcium exchanger currents, but decreased late sodium currents and L-type calcium currents and did not change transient outward currents or inward rectifier potassium currents in LA myocytes. Apelin significantly changed the atrial electrophysiology with a shortening of AP duration, which may be caused by its effects on multiple ionic currents.

Atrial Electrophysiologic Remodeling in Canine Heart Failure: Modulation by Atrial Fibrillation

Background Heart failure (HF) is a common antecedent to atrial fibrillation (AF). Concomitant HF and AF increases morbidity and mortality over that of either disease alone. AF- and HF-induced atrial electrophysiologic remodeling is known to favor the progression of AF. AF results in accelerated repolarization and reductions in multiple ion currents, including transient outward K + current (I to ), changes associated with AF maintenance. Methods Dogs had tachypacing-induced HF for 10 weeks and then were assigned to 6 weeks of atrial tachypacing (60 seconds of pacing at 10 Hz, repeated every 70 seconds) until sustained AF/atrial flutter was induced (HF+AF, n=3), or continued right ventricular tachypacing (n = 6). Baseline LVFS was reduced ( P to were made at 35° ± 0.5°C. Results HF significantly increased I to vs control, whereas HF+AF significantly reduced I to vs control and HF (Figure A). At 2 Hz, HF shortened action potential durations at 50% repolarization (APD 50 ); HF+AF lengthened APD 50 vs HF alone, and did not differ from control (Figure B). HF shortened APD at 90% repolarization (APD 90 ) vs controls, whereas HF+AF had similar shortening of APD 90 . Conclusions Chronic HF results in increased I to and faster repolarization of left atrial appendage myocytes. The addition of AF to chronic HF reduced I to and lengthened APD 50 without changing APD 90 . The effects of chronic HF and chronic HF+AF on I to and APD morphology are variable, suggesting complex disease-induced effects on the substrate for AF.

LYSOPHOSPHATIDIC ACID PROLONGS ACTION POTENTIAL DURATION AND INCREASES ELECTROPHYSIOLOGICAL INSTABILITY OF ADULT RABBIT VENTRICULAR MYOCARDIUM BY AUGMENTING L-TYPE CALCIUM CURRENT

ObjectivesLysophosphatidic acid (LPA) has various actions on cardiovascular system and is widely reported to modulate multiple ion currents in non-myocardiocytes, but little is known about its electrophysiological effects on cardiac...

Lysophosphatidic Acid Increases the Electrophysiological Instability of Adult Rabbit Ventricular Myocardium by Augmenting L-Type Calcium Current

Lysophosphatidic acid (LPA) has diverse actions on the cardiovascular system and is widely reported to modulate multiple ion currents in some cell types. However, little is known about its electrophysiological effects on cardiac myocytes. This study investigated whether LPA has electrophysiological effects on isolated rabbit myocardial preparations. The results indicate that LPA prolongs action potential duration at 90% repolarization (APD90) in a concentration- and frequency-dependent manner in isolated rabbit ventricular myocytes. The application of extracellular LPA significantly increases the coefficient of APD90 variability. LPA increased L-type calcium current (ICa,L) density without altering its activation or deactivation properties. In contrast, LPA has no effect on two other ventricular repolarizing currents, the transient outward potassium current (Ito) and the delayed rectifier potassium current (IK). In arterially perfused rabbit left ventricular wedge preparations, the monophasic action potential duration, QT interval, and Tpeak-end are prolonged by LPA. LPA treatment also significantly increases the incidence of ventricular tachycardia induced by S1S2 stimulation. Notably, the effects of LPA on action potentials and ICa,L are PTX-sensitive, suggesting LPA action requires a Gi-type G protein. In conclusion, LPA prolongs APD and increases electrophysiological instability in isolated rabbit myocardial preparations by increasing ICa,L in a Gi protein-dependent manner.

Suppression of phosphoinositide 3-kinase signaling and alteration of multiple ion currents in drug-induced long QT syndrome.

Many drugs, including some commonly used medications, can cause abnormal heart rhythms and sudden death, as manifest by a prolonged QT interval in the electrocardiogram. Cardiac arrhythmias caused by drug-induced long QT syndrome are thought to result mainly from reductions in the delayed rectifier potassium ion (K(+)) current I(Kr). Here, we report a mechanism for drug-induced QT prolongation that involves changes in multiple ion currents caused by a decrease in phosphoinositide 3-kinase (PI3K) signaling. Treatment of canine cardiac myocytes with inhibitors of tyrosine kinases or PI3Ks caused an increase in action potential duration that was reversed by intracellular infusion of phosphatidylinositol 3,4,5-trisphosphate. The inhibitors decreased the delayed rectifier K(+) currents I(Kr) and I(Ks), the L-type calcium ion (Ca(2+)) current I(Ca,L), and the peak sodium ion (Na(+)) current I(Na) and increased the persistent Na(+) current I(NaP). Computer modeling of the canine ventricular action potential showed that the drug-induced change in any one current accounted for less than 50% of the increase in action potential duration. Mouse hearts lacking the PI3K p110α catalytic subunit exhibited a prolonged action potential and QT interval that were at least partly a result of an increase in I(NaP). These results indicate that down-regulation of PI3K signaling directly or indirectly via tyrosine kinase inhibition prolongs the QT interval by affecting multiple ion channels. This mechanism may explain why some tyrosine kinase inhibitors in clinical use are associated with increased risk of life-threatening arrhythmias.

Ionic mechanisms underlying cardiac toxicity of the organochloride solvent trichloromethane

Trichloromethane (chloroform) is widely used for industrial chemical synthesis and also as an organic solvent in laboratories or ingredient of pesticides. Sudden death resulted from cardiac arrhythmias has been reported in clinic with acute trichloromethane intoxication. The present study was designed to investigate ionic mechanisms underlying arrhythmogenic effect (cardiac toxicity) of trichloromethane in isolated rat hearts and ventricular myocytes and HEK 293 cells stably expressing human Nav1.5, HCN2, or hERG channel using conventional electrophysiological approaches. It was found that trichloromethane (5 mM) induced bradycardia and atrial-ventricular conduction blockade or ventricular fibrillation, and inhibited cardiac contractile function in isolated rat hearts. It shortened action potential duration (APD) in isolated rat ventricular myocytes, and increased the threshold current for triggering action potential, but had no effect on the inward rectifier K + current I K1. However, trichloromethane significantly inhibited the L-type calcium current I Ca.L and the transient outward potassium current I to in a concentration-dependent manner (IC 50s: 1.01 and 2.4 mM, respectively). In HEK 293 cells stably expressing cardiac ion channel genes, trichloromethane reduced hNav1.5, HCN2, and hERG currents with IC 50s of 8.2, 3.3, and 4.0 mM, respectively. These results demonstrate for the first time that trichloromethane can induce bradycardia or ventricular fibrillation, and the arrhythmogenic effect of trichloromethane is related to the inhibition of multiple ionic currents including I Ca.L, I to, I Na, HCN2, and hERG channels.

Recreating Ion Channel IV Curves using Specific Frequency Components

INTRODUCTION: Impedance spectroscopy cannot distinguish between ion channel families. We hypothesized that amplitudes of specific characteristic frequencies will correlate with the current amplitude passed by a specific ion channel families. Previously, we demonstrated the feasibility of this technique using the inward rectifying potassium channel, KIR2.1. In this study, NaV1.5 is used to demonstrate that the technique is applicable to other families of ion channels. METHODS: IV curves were generated using a standard voltage step protocol performed in whole-cell voltage clamp mode on HEK293 cells transiently transfected with SCN5A (encodes NaV1.5). Noise functions containing 1-50 kHz frequencies were inserted into each voltage step. The real component of the Fast Fourier transform (FFT) was then calculated for each trace. Each frequency magnitude as a function of voltage step was correlated with the IV curve. RESULTS: The magnitude of 22.5 and 24.5 kHz correlated well with the IV curve of NaV1.5 in the presence of the noise function (R>0.8), and poorly in the absence of noise (|R|<0.3). Two nodes of zero correlation were also found (11.36 +/- .08 kHz and 36.23 +/- 4.79 kHz. For KIR2.1, current and frequency amplitudes did not correlate well between 11 and 36 kHz, suggesting that this correlation may be unique to NaV1.5. On the other hand, frequencies were identified below 10 kHz whose amplitudes highly correlate with either one or both channels. CONCLUSIONS: These data suggest that specific frequencies exist which can re-create the shape of both KIR2.1 and NaV1.5 IV curves. Furthermore, the correlation at some frequencies is channel specific, while others are not. This methodology could be a powerful tool for assessing the behavior of multiple ionic currents simultaneously during a freely running action potential.

Sequential dissection of multiple ionic currents in single cardiac myocytes under action potential-clamp

The cardiac action potential (AP) is shaped by myriad ionic currents. In this study, we develop an innovative AP-clamp Sequential Dissection technique to enable the recording of multiple ionic currents in the single cell under AP-clamp. This new technique presents a significant step beyond the traditional way of recording only one current in any one cell. The ability to measure many currents in a single cell has revealed two hitherto unknown characteristics of the ionic currents in cardiac cells: coordination of currents within a cell and large variation of currents between cells. Hence, the AP-clamp Sequential Dissection method provides a unique and powerful tool for studying individual cell electrophysiology.

The Antianginal Agent Ranolazine is a Potent Antiarrhythmic Agent that Reduces Ventricular Arrhythmias: Through a Mechanism Favoring Inhibition of Late Sodium Channel

The antianginal agent ranolazine (R) has shown some promise as an antiarrhythmic agent but its mechanism of action is not known. Previously, we have shown that R suppresses ventricular arrhythmias at a concentration >10 μM that may affect multiple ion currents including IKr. The present study was carried out to determine the effects of low dose (4 μM) of R that primarily inhibits late I(Na) on ischemia/reperfusion induced ventricular arrhythmias. We subjected 20 anesthetized rats to 5 min of proximal left coronary artery occlusion followed by 5 min of reperfusion. Rats were randomized to vehicle control (C; n = 10) versus low dose R (n = 10; 3.33 mg/kg i.v. bolus plus 3.2 mg/kg/h R started 20 min prior to occlusion, which yields a concentration of 4 μM, within the known level that blocks late Na channels but well below the level that has effect on IKr or peak I(Na)). Reperfusion-induced arrhythmias were quantitated by electrocardiographic monitoring. In the C group 9/10 rats developed any arrhythmias versus 3/10 in the R group (P = 0.02); 6/10 developed ventricular tachycardia (VT) in the C group versus 0/10 in the R group (P = 0.01). The median number of episodes of VT were 1.5 in the C group versus 0 in the R group (P = 0.005). Sustained VT (>10 sec) occurred in 3/10 C and 0/10 in R (P = 0.21). The median duration of VT was 1.8 seconds in C versus 0 in R (P = 0.005). Ventricular fibrillation occurred in 1/10 in C and 0 in R. Ventricular premature beats (VPBs) occurred in 9/10 C and 3/10 R rats (P = 0.02). The median number of VPBs was 5.5 in the C group versus 0 in R group (P = 0.01). The ischemic risk zones were equivalent in the C and R groups (35 ± 3% and 32 ± 3% of the left ventricle, respectively). In conclusion, data show that the marked antiarrhythmic effect of R in the setting of acute ischemia/reperfusion occurs at low doses consistent with inhibition of late I(Na) .

Dronedarone: A New Generation of Anti- arrhythmic Drug for the Treatment of Atrial Fibrillation

Amiodarone is currently the most effective anti-arrhythmic drug for the treatment of atrial fibrillation. Its chronic use, however, has been associated with serious extra-cardiac adverse effects. Dronedarone is a new anti-arrhythmic drug that does not possess the different organ toxicities associated with amiodarone. With the addition of a methylsulfonyl group and the removal of iodine moieties, dronedarone has lower tissue accumulation and a shorter half-life than amiodarone. Dronedarone is a potent blocker of multiple ion currents, including the rapidly activating delayed-rectifier potassium current, the slowly activating delayed-rectifier potassium current, the inward rectifier potassium current, the acetylcholine activated potassium current, peak sodium current, and L-type calcium current, and exhibits antiadrenergic and coronary vasodilatatory effects. Although less effective than amiodarone as a rhythm-control agent, dronedarone has been shown to reduce ventricular rate and AF recurrence and it is the first anti-arrhythmic drug shown to reduce the combined outcome of cardiovascular mortality and hospitalization in AF patients. Dronedarone, however, is contraindicated in patients with moderate to severe heart failure. The most common side-effects associated with dronedarone are gastrointestinal including nausea, vomiting and diarrhea. This article will review the current evidence of safety and effectiveness of dronedarone in treating patients with atrial fibrillation and the position of this new drug in the currently available anti-arrhythmic armamentarium will be discussed.

Characteristic Frequency Analysis of Inward Rectifier Kir 2.1

INTRODUCTION: Impedance spectroscopy cannot distinguish between ion channel subtypes. We hypothesized that amplitudes of specific characteristic frequencies will correlate with the current amplitude passed by a specific ion channel subtype (characteristic frequency). We chose to test this hypothesis using the human inward rectifying potassium channel, Kir 2.1. METHODS: IV-relationships were generated using a standard voltage step protocol (−140 to 0mV, 7mV steps) performed in whole-cell voltage clamp mode on HEK293 cells stably transfected with KCNJ2, which encodes Kir 2.1. Noise functions containing equal magnitudes of 1-15 kHz frequencies (amplitudes: 25, 50, 75 or 100mV) were inserted into each voltage step. The real component of the Fast Fourier transform (FFT) of the output signal was calculated with and without noise for each step potential. The magnitude of each frequency as a function of voltage step was correlated with the IV-relationship. RESULTS: In the absence of noise (control), magnitudes of all frequencies correlated poorly (|R|<0.15) with the IV relationship. With noise, magnitudes of frequencies between 0.2-1 and 2-4 kHz demonstrated high negative (R < −0.9) and positive correlation (R > 0.9) respectively, with the IV-relationship. Two nodes of zero correlation were also found (1.39 +/- 0.10 kHz and 8.49 +/- 0.74 kHz). Increasing noise amplitude increased the absolute value of the correlation for the aforementioned frequencies without significantly changing the nodes of zero correlation. CONCLUSIONS: These data suggest that the observed frequency response reflects current passing through Kir 2.1 channels. However it remains unknown whether any of these characteristic frequencies are unique to Kir2.1. Identifying characteristic frequencies of other ion channel subtypes could allow simultaneous measurement of multiple ionic currents.