Inhibition Of Late Sodium Current Research Articles

Distinctive electrophysiological characteristics of right ventricular out-flow tract cardiomyocytes.

Ventricular arrhythmias commonly originate from the right ventricular out-flow tract (RVOT). However, the electrophysiological characteristics and Ca2+ homoeostasis of RVOT cardiomyocytes remain unclear. Whole-cell patch clamp and indo-1 fluorometric ratio techniques were used to investigate action potentials, Ca2+ homoeostasis and ionic currents in isolated cardiomyocytes from the rabbit RVOT and right ventricular apex (RVA). Conventional microelectrodes were used to record the electrical activity before and after (KN-93, a Ca2+/calmodulin-dependent kinase II inhibitor, or ranolazine, a late sodium current inhibitor) treatment in RVOT and RVA tissue preparations under electrical pacing and ouabain (Na+/K+ ATPase inhibitor) administration. In contrast to RVA cardiomyocytes, RVOT cardiomyocytes were characterized by longer action potential duration measured at 90% and 50% repolarization, larger Ca2+ transients, higher Ca2+ stores, higher late Na+ and transient outward K+ currents, but smaller delayed rectifier K+, L-type Ca2+ currents and Na+-Ca2+ exchanger currents. RVOT cardiomyocytes showed significantly more pacing-induced delayed afterdepolarizations (22% versus 0%, P < 0.05) and ouabain-induced ventricular arrhythmias (94% versus 61%, P < 0.05) than RVA cardiomyocytes. Consistently, it took longer time (9 ± 1 versus 4 ± 1 min., P < 0.05) to eliminate ouabain-induced ventricular arrhythmias after application of KN-93 (but not ranolazine) in the RVOT in comparison with the RVA. These results indicate that RVOT cardiomyocytes have distinct electrophysiological characteristics with longer AP duration and greater Ca2+ content, which could contribute to the high RVOT arrhythmogenic activity.

Diastolische Herzinsuffizienz

Heart failure with preserved ejection fraction (i.e. diastolic heart failure) accounts for about half of heart failure cases. The aim of this review is to reflect current knowledge regarding the epidemiology, pathophysiology and treatment. Diastolic heart failure patients are principally elderly and predominantly female. Numerous pathophysiological alterations in this disease have been shown and recent therapeutic recommendations include control of cardiovascular risk factors and symptoms. New therapeutic options, such as inhibition of late sodium current, aldosterone receptor blockade, combined inhibition of AT1 receptor and the enzyme neprilysin, and phosphodiesterase 5 inhibition are discussed in this review and ongoing clinical trials are also briefly presented. Diastolic heart failure remains a cardiac disease which is difficult to treat; however, new study results allow a better definition of a population of patients who could benefit from specific therapies.

Late Sodium Current Inhibition: The Most Promising Antiarrhythmic Principle in the Near Future?

Ranolazine has primarily been developed and so far approved as an antianginal drug. However, it also has potentially interesting and relevant antiarrhythmic properties. Its antiarrhythmic effects are mainly based on the blockade of sodium currents, in particular of the late sodium current. Experimental and clinical studies have revealed an antiarrhythmic effect of ranolazine in atrial fibrillation as chronic or "pill in the pocket" therapy. Of note, this effect was preserved in the setting of chronic heart failure. Furthermore, an antiarrhythmic effect has also been shown in experimental models of ventricular tachyarrhythmias. In addition, prevention of ventricular tachyarrhythmias has been demonstrated in patients with structural heart disease. A few late sodium current inhibitors are evaluated for antiarrhythmic properties in experimental studies. However, randomized clinical data is not yet available for these recently developed agents and larger controlled trials are necessary before recommending ranozaline as a novel antiarrhythmic drug.

Effects of Flecainide and Ranolazine on Intracellular Calcium Handling and Sarcolemmal Sodium Current

Flecainide has received considerable interest due to its antiarrhythmic efficacy. However, more detailed analyses of calcium (Ca2+)-dependent processes are required to demonstrate a conclusive mechanism of action. We characterise flecainide's ability to suppress arrhythmogenic Ca2+-waves and examine the involvement of ryanodine receptors in flecainide's antiarrhythmic efficacy, Further, we evaluate the native cardiac sodium channel contribution to flecainide¯s pharmacological profile and compare its actions with a late sodium current inhibitor, ranolazine. Extracellular drug effects on Ca2+-sparks and Ca2+-waves were measured in field-stimulated Fluo-4AM loaded human and rat ventricular cardiomyocytes. Whole-cell sodium currents (INa) were measured before and after a series of high-frequency depolarizing pulses, establishing acute- and use-dependent inhibition, respectively. A therapeutic dose of flecainide (5μM) significantly decreased spark-mediated Ca2+ leak, primarily as a result of reduced Ca2+-spark amplitude (P < 0.001). Following flecainide perfusion spontaneous wave frequency was significantly reduced (P < 0.001), whilst wave-free survival and inter-wave interval were significantly increased (P < 0.01 and P < 0.05, respectively). The late INa blocker ranolazine (10-50μM) was evaluated against flecainide for its potential to inhibit sarcolemmal INa and Ca2+-waves. Under acute application, 5μM flecainide reduced peak INa to 49 ± 7% of control compared to 75 ± 9% and 66 ± 10% with 10μM and 50μM ranolazine respectively. Flecainide showed increased use-dependency, causing 35 ± 5% peak INa inhibition compared to control, while 10μM and 50μM ranolazine resulted in 73 ± 7% and 60 ± 7% reduction, respectively. Furthermore, flecainide's effect on Ca2+-wave frequency show correspondingly higher efficacy (P < 0.001) versus increasing concentrations of ranolazine (P < 0.01). Our results suggest that flecainide normalizes arrythmogenic Ca2+-waves by selectively reducing spark mass and a corresponding wave initiation. Additionally, we draw parallel between the ability of flecainide and ranolazine to suppress arrhythmogenic Ca2+-waves, and establish correlation with membrane sodium influx.

Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts

Enhanced late inward Na current (INa-L) modulates action potential duration (APD) and plays a key role in the genesis of early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs) and triggered activity. The purpose of this study was to define the influence of selective block of INa-L on EAD- and DAD-mediated triggered ventricular tachycardia (VT) and ventricular fibrillation (VF) in intact hearts using (GS967), a selective and potent (IC50 = 0.13 ± 0.01 μM) blocker of INa-L. VT/VF were induced either by local aconitine injection (50 μg) in the left ventricular muscle of adult (3-4 months) male rats (N = 21) or by arterial perfusion of 0.1 mM hydrogen peroxide (H2O2) in aged male rats (24-26 months, N = 16). The left ventricular epicardial surface of the isolated-perfused hearts was optically mapped using fluorescent voltage-sensitive dye, and microelectrode recordings of action potentials were made adjacent to the aconitine injection site. The suppressive and preventive effects of GS967 (1 μM) against EAD/DAD-mediated VT/VF were then determined. Aconitine induced VT in all 13 hearts studied. Activation map (N = 6) showed that the VT was initiated by a focal activity arising from the aconitine injection site (cycle length [CL] 84 ± 12) that degenerated to VF (CL 52 ± 8 ms) within a few seconds. VF was maintained by multifocal activity with occasional incomplete reentrant wavefronts. Administration of GS967 suppressed the VT/VF in 10 of 13 hearts (P < .001). Preexposure to GS967 for 15 minutes before aconitine injection prevented initiation of VT/VF in 5 of 8 additional hearts (P < .02). VF reoccurred within 10 minutes on washout of GS967. Microelectrode recordings (N = 7) showed that VT/VF was initiated by EAD- and DAD-mediated triggered activity at CL of 86 ± 14 ms (NS from VT CL) that preceded the VF. GS967 shortened APD, flattened the slope of the dynamic APD restitution curve, and reduced APD dispersion from 42 ± 12 ms to 8 ± 3 ms (P < .01). H2O2 perfusion in eight fibrotic aged hearts promoted EAD-mediated focal VT/VF, which was suppressed by GS967 in five hearts (P < .02). The selective INa-L blocker GS967 effectively suppresses and prevents aconitine and oxidative stress-induced EADs, DADs, and focal VT/VF. Suppression of EADs, DADs, and reduction of APD dispersion make GS967 a potentially useful antiarrhythmic drug in conditions of enhanced INa-L.

Response to Letter Regarding Article, “Late Sodium Current Inhibition Reverses Electromechanical Dysfunction in Human Hypertrophic Cardiomyopathy”

We thank Sikkel et al for their appreciative letter, particularly focusing on the statistical approach used in our recent work.1 Indeed, physiological parameters of cells from human subjects exhibit considerable and intrinsic interindividual variability, at variance with inbred rodents. Thus, when working on human data, the use of hierarchical statistical analysis is not only the most valid option, but one could say it is mandatory to perform reliable comparisons between normal and diseased states. Hierarchical statistical analysis has been used previously in biomedical research involving human subjects,2 including a recent study comparing mechanical data from single myofibrils isolated from cardiac samples of patients with hypertrophic cardiomyopathy with donor hearts and secondary hypertrophy.3 …

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

Ranolazine in Stable Angina: Mechanism of Action and Therapeutic Implications

Ranolazine, the first member of a newer class of medications, is a piperazine derivative that was first approved by the US Food and Drug Administration in 2006 as a treatment for chronic angina. In 2008, ranolazine received a new indication for the treatment of chronic angina, allowing for its first-line use. Ranolazine's mechanism of action differs fundamentally from that of currently available anti-ischemic drugs, thus introducing a new paradigm to complement what had been considered conventional therapy. This article outlines this mechanism of action, with a focus on myocardial ischemia and on aspects that may assist in fully exploiting ranolazine's therapeutic potential. Although the mechanism of action initially postulated to be responsible for ranolazine's antianginal effect was inhibition of fatty acid oxidation, current evidence suggests alternative explanations. Chief among them is its role as a selective inhibitor of the late component of the Na1 current. The late sodium current has been shown, in several models, to be at the root of a wide spectrum of electrical, contractile, and metabolic derangements.Thus, ranolazine, in addition to its electrophysiologic role, has an influence on cardiomyocyte metabolism, excitation-contraction coupling, and myocardial perfusion. This explains both its efficacy as an antianginal agent and the spectrum of clinical effects observed in human trials, including electrical stabilization and glycemic effects. Accordingly, this article focuses on the current evidence that supports late sodium current inhibition as a plausible mechanism of ranolazine's therapeutic efficacy.

Late Sodium Current Inhibition in Acquired and Inherited Ventricular (dys)function and Arrhythmias

The late sodium current has been increasingly recognized for its mechanistic role in various cardiovascular pathologies, including angina pectoris, myocardial ischemia, atrial fibrillation, heart failure and congenital long QT syndrome. Although relatively small in magnitude, the late sodium current (I(NaL)) represents a functionally relevant contributor to cardiomyocyte (electro)physiology. Many aspects of I(NaL) itself are as yet still unresolved, including its distribution and function in different cell types throughout the heart, and its regulation by sodium channel accessory proteins and intracellular signalling pathways. Its complexity is further increased by a close interrelationship with the peak sodium current and other ion currents, hindering the development of inhibitors with selective and specific properties. Thus, increased knowledge of the intricacies of the complex nature of I(NaL) during distinct cardiovascular conditions and its potential as a pharmacological target is essential. Here, we provide an overview of the functional and electrophysiological effects of late sodium current inhibition on the level of the ventricular myocyte, and its potential cardioprotective and anti-arrhythmic efficacy in the setting of acquired and inherited ventricular dysfunction and arrhythmias.

Late Sodium Current Inhibition Reverses Electromechanical Dysfunction in Human Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM), the most common mendelian heart disorder, remains an orphan of disease-specific pharmacological treatment because of the limited understanding of cellular mechanisms underlying arrhythmogenicity and diastolic dysfunction. We assessed the electromechanical profile of cardiomyocytes from 26 HCM patients undergoing myectomy compared with those from nonfailing nonhypertrophic surgical patients by performing patch-clamp and intracellular Ca(2+) (Ca(2+)(i)) studies. Compared with controls, HCM cardiomyocytes showed prolonged action potential related to increased late Na(+) (I(NaL)) and Ca(2+) (I(CaL)) currents and decreased repolarizing K(+) currents, increased occurrence of cellular arrhythmias, prolonged Ca(2+)(i) transients, and higher diastolic Ca(2+)(i). Such changes were related to enhanced Ca(2+)/calmodulin kinase II (CaMKII) activity and increased phosphorylation of its targets. Ranolazine at therapeutic concentrations partially reversed the HCM-related cellular abnormalities via I(NaL) inhibition, with negligible effects in controls. By shortening the action potential duration in HCM cardiomyocytes, ranolazine reduced the occurrence of early and delayed afterdepolarizations. Finally, as a result of the faster kinetics of Ca(2+)(i) transients and the lower diastolic Ca(2+)(i), ranolazine accelerated the contraction-relaxation cycle of HCM trabeculae, ameliorating diastolic function. We highlighted a specific set of functional changes in human HCM myocardium that stem from a complex remodeling process involving alterations of CaMKII-dependent signaling, rather than being a direct consequence of the causal sarcomeric mutations. Among the several ion channel and Ca(2+)(i) handling proteins changes identified, an enhanced I(NaL) seems to be a major contributor to the electrophysiological and Ca(2+)(i) dynamic abnormalities of ventricular myocytes and trabeculae from patients with HCM, suggesting potential therapeutic implications of I(NaL) inhibition.

Anti-Anginal and Anti-Ischemic Effects of Late Sodium Current Inhibition

The effective treatment of coronary artery disease targets two distinct goals, controlling symptomatic angina and decreasing the adverse events associated with ischemia. Traditional anti-anginal and anti-ischemic drugs function by altering the determinants of myocardial oxygen supply or demand, usually by altering loading conditions, changing the heart rate, or impacting contractility. Blockade of the late inward sodium current, late I(Na), offers another target for the treatment of ischemia. Blockade of late I(Na) reduces the sodium and calcium overload that follows ischemia. This improves myocardial relaxation and reduces left ventricular diastolic stiffness, in turn enhancing myocardial contractility and perfusion. Ranolazine, a late I(Na) inhibitor, has been shown to provide both anti-anginal and anti-ischemic benefits without significant alterations in the heart rate and blood pressure in patients with stable coronary artery disease. When evaluated in patients with acute coronary syndrome, ranolazine has been shown to decrease recurrent ischemia, but not significantly reduce the risk of death or myocardial infarction. This review will address the rationale that inhibition of the late sodium current is beneficial in reducing cardiac dysfunction during ischemia, and discuss the clinical studies supporting the use of ranolazine for its anti-anginal and anti-ischemic effects.

Rethinking of Metabolic Approach in Heart Failure

Although neurohumoral antagonism has successfully reduced HF morbidity and mortality, the residual risk remains unacceptably high. The concept of myocardial energetic deficiency in the pathogenesis of HF, and the consequent rationale for treating this energy deficiency clinically by metabolic modulation using long-chain 3-ketoacyl coenzyme A thiolase inhibitior (e.g., trimetazidine), late sodium current inhibitor (e.g., ranolazine), carnitine palmitoyl transferase inhibitior (e.g., perhexiline) and carnitine palmitoyl transferase I and/or II inhibitors (e.g., etomoxir) would be recognized.

TCT-719 Effects of ranolazine in patients with acute coronary syndrome and stable angina according to whether they undergo percutaneous coronary intervention: Observations from the MERLIN-TIMI 36 Trial

Ranolazine is a late sodium current (late INa) inhibitor with anti-ischemic effects that is indicated for the treatment of stable angina. Patients with a history stable angina who subsequently are admitted with ACS are at particularly high risk of recurrent ischemic events. We examined the 1-year

A Novel, Potent, and Selective Inhibitor of Cardiac Late Sodium Current Suppresses Experimental Arrhythmias

Inhibition of cardiac late sodium current (late I(Na)) is a strategy to suppress arrhythmias and sodium-dependent calcium overload associated with myocardial ischemia and heart failure. Current inhibitors of late I(Na) are unselective and can be proarrhythmic. This study introduces GS967 (6-[4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine), a potent and selective inhibitor of late I(Na), and demonstrates its effectiveness to suppress ventricular arrhythmias. The effects of GS967 on rabbit ventricular myocyte ion channel currents and action potentials were determined. Anti-arrhythmic actions of GS967 were characterized in ex vivo and in vivo rabbit models of reduced repolarization reserve and ischemia. GS967 inhibited Anemonia sulcata toxin II (ATX-II)-induced late I(Na) in ventricular myocytes and isolated hearts with IC(50) values of 0.13 and 0.21 µM, respectively. Reduction of peak I(Na) by GS967 was minimal at a holding potential of -120 mV but increased at -80 mV. GS967 did not prolong action potential duration or the QRS interval. GS967 prevented and reversed proarrhythmic effects (afterdepolarizations and torsades de pointes) of the late I(Na) enhancer ATX-II and the I(Kr) inhibitor E-4031 in isolated ventricular myocytes and hearts. GS967 significantly attenuated the proarrhythmic effects of methoxamine+clofilium and suppressed ischemia-induced arrhythmias. GS967 was more potent and effective to reduce late I(Na) and arrhythmias than either flecainide or ranolazine. Results of all studies and assays of binding and activity of GS967 at numerous receptors, transporters, and enzymes indicated that GS967 selectively inhibited late I(Na). In summary, GS967 selectively suppressed late I(Na) and prevented and/or reduced the incidence of experimentally induced arrhythmias in rabbit myocytes and hearts.

Late Sodium Current Inhibition Alone with Ranolazine Is Sufficient to Reduce Ischemia- and Cardiac Glycoside-Induced Calcium Overload and Contractile Dysfunction Mediated by Reverse-Mode Sodium/Calcium Exchange

Excessive reverse-mode (RM) sodium/calcium exchanger 1.1 (NCX1.1) activity, resulting from intracellular sodium accumulation caused by reduced Na+/K+-ATPase activity, increased Na-H exchanger 1 activity. The induction of the voltage-gated sodium channel late current component (late INa), is a major pathway for intracellular calcium (Ca2+i) loading in cardiac ischemia-reperfusion (IR) injury and cardiac glycoside toxicity. Inhibition of late INa with the antianginal agent ranolazine is protective in models of IR injury and cardiac glycoside toxicity. However, whether inhibition of late INa alone is sufficient to provide maximal protection or additional inhibition of RM NCX1.1 provides further benefit remains to be determined conclusively. Therefore, the effects of ranolazine were compared with the INa inhibitor lidocaine in models of IR injury and ouabain toxicity, RM NCX1.1-mediated Ca2+ overload, and patch-clamp assays of RM NCX1.1 currents. Ranolazine and lidocaine (10 μM) similarly reduced Ca2+i overload and improved left ventricle work recovery in whole-heart models of IR injury or exposure to ouabain (80 μM). Ranolazine (10 μM), but not lidocaine (10 μM), reduced RM NCX1.1-mediated Ca2+i overload in ventricular myocytes. Furthermore, ranolazine inhibited RM NCX1.1 currents (IC50 1.7 μM), without affecting forward mode currents, revealing that ranolazine has novel RM NCX1.1 inhibitory actions. However, because lidocaine provides similar protection to ranolazine in whole-heart models but does not inhibit RM NCX1.1, we conclude that induction of late INa is upstream of RM NCX1.1 activity and selective inhibition of late INa alone is sufficient to reduce Ca2+i overload and contractile dysfunction in IR injury and cardiac glycoside toxicity.

Modulation of the late sodium current by ATX-II and ranolazine affects the reverse use-dependence and proarrhythmic liability of IKrblockade

Drug-induced torsades de pointes (TdP) often occurs during bradycardia due to reverse use-dependence. We tested the hypothesis that inhibition or enhancement of late sodium current (I(Na,L) ) could modulate the drug-induced reverse use-dependence in QT and T(p-e) (an index of dispersion of repolarization), and therefore the liability for TdP. Arterially perfused rabbit left ventricular wedge preparations were used. Action potentials from the endocardium were recorded simultaneously with a transmural ECG. The effects of Anemonia sulcata toxin (ATX-II) (an I(Na,L) enhancer), d,l-sotalol, clarithromycin and ranolazine (an I(Na,L) blocker) on rate-dependent changes in QT, T(p-e) and proarrhythmic events were tested, either alone or in combination. Rate-dependent QT and T(p-e) slopes and TdP score (a combined index of TdP liability) were calculated at control and during drug infusion. ATX-II (30 nM) and sotalol (300 µM) caused a marked increase in QT and T(p-e) intervals, steeper QT-basic cycle length (BCL) and T(p-e) -BCL slopes (i.e. reverse use-dependence), and TdP. Addition of ranolazine (15 µM) to ATX-II or sotalol significantly attenuated QT-BCL, T(p-e) -BCL slopes and the increased TdP scores. In contrast, clarithromycin (100 µM) moderately prolonged QT and T(p-e) without causing R-on-T extrasystole or TdP, but addition of ATX-II (1 nM) to clarithromycin markedly amplified the QT-BCL and T(p-e) -BCL slopes and further increased TdP score. Modulation of I(Na,L) altered drug-induced reverse use-dependence related to QT as well as T(p-e) , indicating that inhibition of I(Na,L) can markedly reduce the TdP liability of agents that prolong QT intervals.

Ion Channel Therapy of Ischemic Heart Disease: From Calcium Channel Blockers to Late Sodium Current Inhibition

What is summarized below relates to the clinical usefulness of various ion channel antagonists reviewed by a clinical cardiologist, not a basic scientist working on ion channel biology.

Ranolazine, a late sodium current inhibitor, reduces ischemia‐induced superoxide emission and improves functional recovery in guinea pig isolated hearts

Ranolazine (RAN) is believed to block a late Na+ (NaL) current that may be activated by reactive oxygen species (ROS) via peroxidation in cardiac cells during ischemia. Na+ loading contributes to cell Ca2+ loading via Na+/Ca2+ exchange (NCE) and cell damage on reperfusion. We tested if RAN treatment during ischemia improves cardiac function on reperfusion and reduces superoxide (O2 ?−) emission. Left ventricular pressure (LVP) and coronary flow (CF) were measured in guinea pig isolated hearts perfused with Krebs‐Ringer's solution; O2 ?− emission was assessed in the LV wall, on‐line, by fluorescence spectrophotometry using DHE. RAN (5 µM), infused for 1 min before 30 min global ischemia, itself decreased heart rate by 20% and LVP by 30% and increased CF by 20%. During late ischemia O2▸− emission increased less with RAN (20% vs. 40% control). At 15 min reperfusion O2▸− emission was reduced 20% by RAN vs. control. At 120 min reperfusion the RAN group (vs. control) exhibited higher LVP (68% vs. 55%) and CF (72% vs. 58%), and reduced incidence of V fibrillation (16% vs. 100%). Ischemia and consequent ROS release are believed to induce a persistent NaL current so blocking this current may reduce Ca2+ loading via NCE. These studies suggest a link between ROS‐induced Na+ loading via NaL and LV function during reperfusion. The decrease in O2▸− emission with RAN during ischemia is likely secondary to improved mitochondrial bioenergetics.

Abstract 2316: Ranolazine, a Late Sodium Current Inhibitor, as an Adjunct to Cardioplegia Further Reduces Contracture during Ischemia and Reperfusion

Although cardioplegia (CP) protects myocardium during ischemic cardiac arrest, cardioplegic preservation can be suboptimal for increasingly complex cardiac surgical patients. Ranolazine (Ran), a novel antianginal agent, was recently shown to mitigate ischemia-induced Ca 2+ overload via its inhibitory effects on the late Na + current, but the benefit of Ran during cardioplegic arrest is not known. The purpose of the study was to investigate the therapeutic potential of Ran as an adjunct to CP. Hearts isolated from female Sprague-Dawley rats were Langendorff-perfused and exposed to normothermic global ischemia for 40 min followed by 30-min reperfusion (I/R). Three groups were studied: control buffer (n = 10); crystalloid CP (Fremes, n = 12); CP supplemented with Ran (n = 12). CP was bolus-injected with or without Ran at the time of ischemia. End-diastolic pressure (EDP), developed pressure, dP/dt min , and dP/dt max were measured throughout the study. CP significantly delayed onset of ischemic contracture (defined as a time to 20 mmHg of EDP), compared to control (25 ± 2 min in CP alone vs. 12 ± 1 min in control, p &lt; 0.05). Ran added to CP further delayed the time to contracture (34 ± 2 min in Ran, p &lt; 0.05 compared to CP alone). Consistent with these findings, the area under the diastolic pressure curve during the entire period of ischemia was significantly smaller in CP + Ran versus CP alone (p &lt; 0.05). I/R caused dramatic elevations in EDP during reperfusion. CP lessened the extent of the reperfusion contracture (32 ± 3 mmHg in CP alone vs. 76 ± 3 mmHg in control, p &lt; 0.05). Addition of Ran to CP further lessened the contracture (17 ± 2 mmHg in Ran, p &lt; 0.05 compared to CP alone). I/R severely depressed systolic cardiac contractile function. The impairment in contractile function was significantly reduced by CP, as well as CP + Ran, but there was no statistical difference between the two groups. While CP alone reduced the onset of cardiac contracture in this model of I/R, addition of Ran to CP further enhanced the cardioprotection. These results suggest the potential therapeutic efficacy of Ran as an adjunct to CP and further support the protective role of late Na + current inhibition.

Sodium Late Current Blockers in Ischemia Reperfusion: Is the Bullet Magic?

We describe the discovery of the first selective, potent, and voltage-dependent inhibitor of the late current mediated by the cardiac sodium channel Na V1.5. The compound 3,4-dihydro- N-[(2 S)-3-[(2-methoxyphenyl)thio]-2-methylpropyl]-2 H-(3 R)-1,5-benzoxathiepin-3-amine, 2a (F 15845), was identified from a novel family of 3-amino-1,5-benzoxathiepine derivatives. The late sodium current inhibition and antiischemic effects of 2a were studied in various models in vitro and in vivo. In a rabbit model of ischemia-reperfusion, 2a exhibited more potent antiischemic effects than reference compounds KC 12291, ranolazine, and ivabradine. Thus, after a single administration, 2a almost abolished ST segment elevation in response to a transient coronary occlusion. Further, the antiischemic activity of 2a is maintained over a wide range of doses and is not associated with any hemodynamic changes, contrary to conventional antiischemic agents. The unique pharmacological profile of 2a opens new and promising opportunities for the treatment of ischemic heart diseases.