RESUMO
There is a need for more efficient pharmacological cardioversion of atrial fibrillation (AF). We tested the hypothesis that inhibition of IK1 significantly enhances the efficacy of INa block to depress atrial excitability and to cardiovert AF. The study was conducted in canine isolated arterially-perfused right atrial preparations with rim of ventricular tissue. AF was induced in the presence of acetylcholine (ACh; 0.5 µM). BaCl2 (10 µM) was used to inhibit IK1 and flecainide (1.5 µM) to block INa. Sustained AF (>45 min) was recorded in 100% atria (5/5) in the presence of ACh alone. Flecainide cardioverted AF in 50% of atria (4/8), BaCl2 in 0% (0/5), and their combination in 100% (5/5). AF cardioversion occurred in 15±9 min with flecainide alone (n=4) and in 8±9 min with the combination (n=5). Following drug-induced AF cardioversion, AF was inducible in 4/4 atria with flecainide alone (≤ 5 min duration) and in 2/5 atria with the combination (≤ 30 sec duration). Atrial excitability was significantly more depressed by combined vs. mono- therapies. There was little to no effect on ventricular excitability under any condition tested. Thus, inhibition of IK1 significantly enhances the efficacy of flecainide to depress atrial excitability and to cardiovert AF in our experimental setting. A combination of INa and IK1 inhibition may be an effective approach for cardioversion of AF.
RESUMO
ABSTRACT: Cancer therapy has made major progress in the past several decades, but treatments are often accompanied by significant side effects. Arrhythmias are a widespread complication of some antineoplastic drugs, with atrial fibrillation (AF) being the most often encountered drug-associated arrhythmia. Preexisting AF risk factors are commonly present in cancer patients who develop drug-associated AF, and active cancer itself may cause or promote AF. Although anticancer drugs may induce AF in cancer patients without AF risk factors, it appears that most drug-associated AF develop when cancer drugs add or aggravate precancer-existing and/or cancer-related pro-AF factors/alterations, additively or synergistically producing AF. Abnormalities in intracellular calcium activity seem to be involved in the generation of anticancer drug-induced AF. In cancer survivors with cancer therapy-induced cardiomyopathy, AF often occurs, with most of the arrhythmias likely to develop secondary to the cardiomyopathy. AF may lead to modification or even cessation of cancer therapy. The management of AF in patients with cancer is currently conducted largely based on pragmatic assumptions. This review briefly discusses AF caused by anticancer drugs and the underlying mechanisms.
Assuntos
Antineoplásicos , Fibrilação Atrial , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Antiarrítmicos/farmacologia , Antineoplásicos/efeitos adversos , Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Cálcio , HumanosRESUMO
Antiarrhythmic drugs remain the mainstay therapy for patients with atrial fibrillation (AF). A major disadvantage of the currently available anti-AF agents is the risk of induction of ventricular proarrhythmias. Aiming to reduce this risk, several atrial-specific or -selective ion channel block approaches have been introduced for AF suppression, but only the atrial-selective inhibition of the sodium channel has been demonstrated to be valid in both experimental and clinical studies. Among the other pharmacological anti-AF approaches, "upstream therapy" has been prominent but largely disappointing, and pulmonary delivery of anti-AF drugs seems to be promising. Major contradictions exist in the literature about the electrophysiological mechanisms of AF (ie, reentry or focal?) and the mechanisms by which anti-AF drugs terminate AF, making the search for novel anti-AF approaches largely empirical. Drug-induced termination of AF may or may not be associated with prolongation of the atrial effective refractory period. Anti-AF drug research has been largely based on the "suppress reentry" ideology; however, results of the AF mapping studies increasingly indicate that nonreentrant mechanism(s) plays an important role in the maintenance of AF. Also, the analysis of anti-AF drug-induced electrophysiological alterations during AF, conducted in the current study, leans toward the focal source as the prime mechanism of AF maintenance. More effort should be placed on the investigation of pharmacological suppression of the focal mechanisms.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/farmacologia , Fibrilação Atrial/tratamento farmacológico , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Animais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Bloqueadores dos Canais de Potássio/farmacologia , Período Refratário Eletrofisiológico/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologiaRESUMO
The mechanisms underlying atrial-selective prolongation of effective refractory period (ERP) and suppression of atrial fibrillation (AF) by NS8593 and UCL1684, small conductance calcium-activated potassium (SK) channel blockers, are poorly defined. The purpose of the study was to confirm the effectiveness of these agents to suppress AF and to probe the underlying mechanisms. Transmembrane action potentials and pseudoelectrocardiograms were recorded from canine isolated coronary-perfused canine atrial and ventricular wedge preparations. Patch clamp techniques were used to record sodium channel current (INa) in atrial and ventricular myocytes and human embryonic kidney cells. In both atria and ventricles, NS8593 (3-10 µM) and UCL1684 (0.5 µM) did not significantly alter action potential duration, suggesting little to no SK channel inhibition. Both agents caused atrial-selective: (1) prolongation of ERP secondary to development of postrepolarization refractoriness, (2) reduction of Vmax, and (3) increase of diastolic threshold of excitation (all are sodium-mediated parameters). NS8593 and UCL1684 significantly reduced INa density in human embryonic kidney cells as well as in atrial but not in ventricular myocytes at physiologically relevant holding potentials. NS8593 caused a shift of steady-state inactivation to negative potentials in atrial but not ventricular cells. NS8593 and UCL1684 prevented induction of acetylcholine-mediated AF in 6/6 and 8/8 preparations, respectively. This anti-AF effect was associated with strong rate-dependent depression of excitability. The SK channel blockers, NS8593 and UCL1684, are effective in preventing the development of AF due to potent atrial-selective inhibition of INa, causing atrial-selective prolongation of ERP secondary to induction of postrepolarization refractoriness.
Assuntos
1-Naftilamina/análogos & derivados , Alcanos/farmacologia , Antiarrítmicos/farmacologia , Fibrilação Atrial/prevenção & controle , Átrios do Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.5/efeitos dos fármacos , Compostos de Quinolínio/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , 1-Naftilamina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Cães , Feminino , Células HEK293 , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Período Refratário Eletrofisiológico/efeitos dos fármacos , Canais de Potássio Ativados por Cálcio de Condutância Baixa/antagonistas & inibidores , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismoRESUMO
Atrial fibrillation (AF) affects 10-50% of patients with chronic heart failure (HF) and is associated with poor long-term prognosis. AF is commonly associated with atrial structural remodeling (ASR), principally characterized by atrial dilatation and fibrosis. However, the occurrence of AF in the full spectrum of ASR encountered in patients with HF is poorly defined. Experimental studies have presented evidence that extensive ASR can be accompanied with a reduced burden of AF, secondary to a prominent depression of atrial excitability. This reduction in AF burden is associated with severe atrial fibrosis rather than with dilatation. Clinical studies of patients with HF point to the possibility that advanced ASR is associated with a less frequent AF occurrence than moderate ASR. Our goal in this review is to introduce the hypothesis that AF is less likely to occur in severe versus moderate atrial ASR in the setting of HF and that it is severe atrial fibrosis-associated depression of atrial excitability that reduces AF burden.
Assuntos
Fibrilação Atrial/fisiopatologia , Fibrose Endomiocárdica/fisiopatologia , Átrios do Coração/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Animais , HumanosRESUMO
Late sodium channel current (late INa) is considered to be an antiarrhythmic target. The prime antiarrhythmic mechanisms of late INa inhibition have been suggested to be (1) suppression of intracellular calcium [Cai]-mediated rhythmic activity (through reduction in Cai secondary to the decrease in intracellular sodium [Nai]) and (2) normalization of repolarization. Endogenous late INa is a small current and acceleration of the heart rate decreases late INa density. Late INa influx may significantly contribute to Nai loading, but it seems to largely occur under the combined conditions of augmented late INa density, bradycardia, and prolonged repolarization. At the same time, the relative contribution of late INa (including endogenous) in any type of prolonged cardiac repolarization is critical. Sodium channel blockers inhibit both late INa and peak INa, and a specific block of late INa might be achieved at slow and normal but seems not at rapid activation rates, at which peak INa, a much greater current, is also likely to be inhibited. The antiarrhythmic potential of a specific inhibition of late INa seems to best fit for, or may be limited to, the prevention of arrhythmias associated with prolonged repolarization, but it seems to be applicable to all types of arrhythmic abnormalities with elongated cardiac repolarization.
Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Bloqueadores dos Canais de Sódio/uso terapêutico , Canais de Sódio/fisiologia , Animais , Antiarrítmicos/farmacologia , Fibrilação Atrial/fisiopatologia , Humanos , Ranolazina/farmacologia , Ranolazina/uso terapêutico , Bloqueadores dos Canais de Sódio/farmacologiaRESUMO
BACKGROUND: There is a need for improved approaches to rhythm control therapy of atrial fibrillation (AF). METHODS: The effectiveness of flecainide (1.5 µmol/L) and ibutilide (20 nmol/L), alone and in combination, to cardiovert and prevent AF recurrence was studied in canine-isolated coronary-perfused right atrioventricular preparations. We also examined the safety of the combination of flecainide (1.5 µmol/L) and ibutilide (50 nmol/L) using canine left ventricular wedge preparations. RESULTS: Sustained AF (>1 hour) was inducible in 100%, 60%, 20%, and 0% of atria in the presence of acetylcholine alone, acetylcholine+ibutilide, acetylcholine+flecainide, and acetylcholine+ibutilide+flecainide, respectively. When used alone, flecainide and ibutilide cardioverted sustained AF in 40% and 20% of atria, respectively, but in 100% of atria when used in combination. Ibutilide prolonged atrial and ventricular effective refractory period by 15% and 8%, respectively, at a cycle length of 500 ms (P<0.05 for both). Flecainide increased the effective refractory period in atria by 27% (P<0.01) but by only 2% in the ventricles. The combination of the 2 drugs lengthened the effective refractory period by 42% in atria (P<0.01) but by only 7% (P<0.05) in the ventricles. In left ventricular wedges, ibutilide prolonged QT and Tpeak-Tend intervals by 25 and 55%, respectively (P<0.05 for both; cycle length, 2000 ms). The addition of flecainide (1.5 µmol/L) partially reversed these effects (P<0.05 for both parameters versus ibutilide alone). Torsades de Pointes score was relatively high with ibutilide alone and low with the drug combination. CONCLUSIONS: In our experimental model, a combination of flecainide and ibutilide significantly improves cardioversion and prevents the recurrence of AF compared with monotherapies with little to no risk for the development of long-QT-mediated ventricular proarrhythmia.
Assuntos
Fibrilação Atrial , Síndrome do QT Longo , Sulfonamidas , Animais , Cães , Flecainida/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/prevenção & controle , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Acetilcolina , Síndrome do QT Longo/tratamento farmacológicoRESUMO
BACKGROUND: Developmental changes in the electrical characteristics of the ventricular myocardium are not well defined. This study examines the contribution of inwardly rectifying K(+) current (IK1), transient outward K(+) current (Ito), delayed rectifier K(+) currents (IKr and IKs) and sodium channel current (INa) to repolarization in the canine neonate myocardium. METHODS: Single myocytes isolated from the left ventricle of 2-3week old canine neonate hearts were studied using patch-clamp techniques. RESULTS: Neonate cells were ~6-fold smaller than those of adults (28.8±8.8 vs. 176±6.7pF). IK1 was larger in neonate myocytes and displayed a substantial inward component and an outward component with negative slope conductance, peaking at -60mV (4.13 pA/pF). IKr tail currents (at -40mV), were small (<20pA). IKs could not be detected, even after exposure to isoproterenol (100nM). Ito was also absent in the neonate, consistent with the absence of a phase 1 in the action potential. Peak INa, late INa and ICa were smaller in the neonate compared with adults. KCND3, KCNIP2 and KCNQ1 mRNA expression was half, while KCNH2 was equal and KCNJ2 was greater in the neonate when compared with adults. CONCLUSIONS: Two major repolarizing K(+) currents (IKs and Ito) present in adult ventricular cells are absent in the 2week old neonate. Peak and late INa are significantly smaller in the neonate. Our results suggest that the absence of these two currents in the neonate heart may increase the susceptibility to arrhythmias under certain long QT conditions.
Assuntos
Canais Iônicos/genética , Canais Iônicos/metabolismo , Função Ventricular/fisiologia , Potenciais de Ação , Animais , Animais Recém-Nascidos , Antiarrítmicos/farmacologia , Cálcio/metabolismo , Cães , Feminino , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Humanos , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Técnicas de Patch-Clamp , Piperidinas/farmacologia , Potássio/metabolismo , Canais de Potássio/fisiologia , Piridinas/farmacologia , Sódio/metabolismo , Função Ventricular/efeitos dos fármacosRESUMO
The anti-arrhythmic efficacy of the late sodium channel current (late I(Na)) inhibition has been convincingly demonstrated in the ventricles, particularly under conditions of prolonged ventricular repolarization. The value of late I(Na) block in the setting of atrial fibrillation (AF) remains poorly investigated. All sodium channel blockers inhibit both peak and late I(Na) and are generally more potent in inhibiting late vs. early I(Na). Selective late I(Na) block does not prolong the effective refractory period (ERP), a feature common to practically all anti-AF agents. Although the late I(Na) blocker ranolazine has been shown to be effective in suppression of AF, it is noteworthy that at concentrations at which it blocks late I(Na) in the ventricles, it also potently blocks peak I(Na) in the atria, thus causing rate-dependent prolongation of ERP due to development of post-repolarization refractoriness. Late I(Na) inhibition in atria is thought to suppress intracellular calcium (Ca(i))-mediated triggered activity, secondary to a reduction in intracellular sodium (Na(i)). However, agents that block late I(Na) (ranolazine, amiodarone, vernakalant, etc) are also potent atrial-selective peak I(Na) blockers, so that the reduction of Na(i) loading in atrial cells by these agents can be in large part due to the block of peak I(Na). The impact of late I(Na) inhibition is reduced by the abbreviation of the action potential that occurs in AF patients secondary to electrical remodeling. It stands to reason that selective late I(Na) block may contribute more to inhibition of Ca(i)-mediated triggered activity responsible for initiation of AF in clinical pathologies associated with a prolonged atrial APD (such as long QT syndrome). Additional studies are clearly needed to test this hypothesis.
Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Bloqueadores dos Canais de Sódio/uso terapêutico , Canais de Sódio/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Antiarrítmicos/administração & dosagem , Fibrilação Atrial/metabolismo , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Bloqueadores dos Canais de Sódio/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Cardioversion of atrial fibrillation (AF) is a common clinical necessity, and there is a need for more effective and safe options for acute cardioversion of AF. OBJECTIVE: The purpose of this study was to test the hypothesis that the efficacy and time course of AF cardioversion by sodium channel current (INa) block can be improved by mild elevation of extracellular potassium ([K+]0). METHODS: Using a canine acetylcholine (ACh)-mediated AF model (isolated coronary-perfused right atrial preparations with a rim of right ventricle), we evaluated the ability of flecainide to suppress AF in the presence of [K+]0 ranging from 3 to 8 mM. RESULTS: At [K+]0 of 4 mM (baseline), persistent AF (>1 hour) was induced in 5 of 5 atria in the presence of 0.5 µM ACh. Flecainide alone (1.5 µM) cardioverted 3 of 6 atria at 4 mM [K+]0, 1 of 6 atria at 3 mM [K+]0, 5 of 5 atria at 5 mM and 6 mM [K+]0, and 4 of 4 atria at 8 mM [K+]0. In the absence of flecainide, an increase in [K+]0 from 4 mM to 5, 6, and 8 mM terminated AF in 0 of 5, 2 of 6, and 4 of 4 atria, respectively. The time to conversion was also abbreviated by elevation of [K+]0. After AF termination with flecainide plus elevated [K+]0, AF was either not inducible or brief (<100 seconds). Combined flecainide and elevated [K+]0 (6 mM) caused an atrial preferential depression of excitability. CONCLUSION: Our findings suggest that a combination of INa block accompanied by mild elevation of serum potassium may be a novel approach to more effectively, rapidly, and safely cardiovert AF and prevent its recurrence in the short term.
Assuntos
Fibrilação Atrial , Animais , Cães , Flecainida/farmacologia , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Átrios do Coração , Canais de SódioRESUMO
Atrial fibrillation (AF) is a very common cardiac arrhythmia with an estimated prevalence of 33.5 million patients globally. It is associated with an increased risk of death, stroke and peripheral embolism. Although genetic studies have identified a growing number of genes associated with AF, the definitive impact of these genetic findings is yet to be established. Several mechanisms, including electrical, structural and neural remodelling of atrial tissue, have been proposed to contribute to the development of AF. Despite over a century of exploration, the molecular and cellular mechanisms underlying AF have not been fully established. Current antiarrhythmic drugs are associated with a significant rate of adverse events and management of AF using ablation is not optimal, especially in cases of persistent AF. This review discusses recent advances in our understanding and management of AF, including new concepts of epidemiology, genetics and pathophysiological mechanisms. We review the current status of antiarrhythmic drug therapy for AF, new potential agents, as well as mechanism-based AF ablation. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.
Assuntos
Fibrilação Atrial , Humanos , Fibrilação Atrial/etiologia , Fibrilação Atrial/genética , Pesquisa Translacional Biomédica , Antiarrítmicos/uso terapêutico , Frequência CardíacaRESUMO
Ranolazine has been shown to produce atrial-selective depression of sodium channel-dependent parameters and suppress atrial fibrillation (AF) in a variety of experimental models. The present study contrasts the effects of ranolazine and those of a clinically used anti-AF class IC agent, propafenone. Electrophysiological and anti-AF effects of propafenone and ranolazine were compared at clinically relevant concentrations (i.e., 0.3-1.5 and 1-10 µM, respectively) in canine isolated coronary-perfused atrial and ventricular preparations. Transmembrane action potential and pseudo-ECG were recorded. Both ranolazine and propafenone produced atrial-selective prolongation of action potential duration. Propafenone depressed sodium channel-mediated parameters [maximum rate of rise of the action potential upstroke (V(max)), conduction time, and diastolic threshold of excitation] and induced postrepolarization refractoriness to a greater degree than ranolazine, and these effects, unlike those induced by ranolazine, were not or only mildly atrial-selective at normal rates (cycle length 500 ms). At fast pacing rates, however, the effects of propafenone on V(max) and conduction time became atrial-selective, because of the elimination of diastolic interval in atria, but not in ventricles. Propafenone (1.5 µM) and ranolazine (10.0 µM) were effective in preventing the initiation of persistent acetylcholine-mediated AF (6/7 and 9/11 atria, respectively), its termination (8/10 and 8/12 atria, respectively), and subsequent reinduction (8/8 and 7/8 atria, respectively). Thus, propafenone and ranolazine both suppress AF, but ranolazine, unlike propafenone, does it with minimal effects on ventricular myocardium, suggesting a reduced potential for promoting ventricular arrhythmias.
Assuntos
Acetanilidas/farmacologia , Antiarrítmicos/farmacologia , Fibrilação Atrial/tratamento farmacológico , Piperazinas/farmacologia , Propafenona/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Fibrilação Atrial/fisiopatologia , Diástole/fisiologia , Cães , Fenômenos Eletrofisiológicos , Átrios do Coração/efeitos dos fármacos , Sistema de Condução Cardíaco/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Cinética , Ranolazina , Período Refratário Eletrofisiológico/efeitos dos fármacosRESUMO
The action of AVE0118 to prolong effective refractory period (ERP) in atria but not in ventricles is thought to be due to its inhibition of IKur. However, in nonremodeled atria, AVE0118 prolongs ERP but not action potential duration (APD70-90), which can be explained with the inhibition of sodium but not potassium channel current. ERP, APD, and the maximum rate of increase of the AP upstroke (Vmax) were measured in the canine-isolated coronary-perfused right atrial and in superfused ventricular tissue preparations. Whole-cell patch-clamp techniques were used to measure sodium channel current in HEK293 cells stably expressing SCN5A. AVE0118 (5-10 µM) prolonged ERP (P < 0.001) but not APD70 and decreased Vmax (by 15%, 10 µM, P < 0.05; n = 10 for each). Ventricular ERP, APD90, and Vmax were not changed significantly by 10 µM AVE0118 (all P = ns; n = 7). AVE0118 effectively suppressed acetylcholine-mediated persistent atrial fibrillation. AVE0118 (10 µM) reduced peak current amplitude of SCN5A-WT current by 36.5% ± 6.6% (P < 0.01; n = 7) and shifted half-inactivation voltage (V0.5) of the steady-state inactivation curve from -89.9 ± 0.5 to -96.0 ± 0.9 mV (P < 0.01; n = 7). Our data suggest that AVE0118-induced prolongation of atrial, but not ventricular ERP, is due largely to atrial-selective depression of sodium channel current, which likely contributes to the effectiveness of AVE0118 to suppress atrial fibrillation.
Assuntos
Compostos de Bifenilo/farmacologia , Período Refratário Eletrofisiológico/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/efeitos dos fármacos , Acetilcolina/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/metabolismo , Compostos de Bifenilo/administração & dosagem , Cães , Relação Dose-Resposta a Droga , Células HEK293 , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Humanos , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/administração & dosagem , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Bloqueadores dos Canais de Sódio/administração & dosagem , Canais de Sódio/intoxicaçãoRESUMO
BACKGROUND: Oliceridine is a biased ligand at the µ-opioid receptor recently approved for the treatment of acute pain. In a thorough QT study, corrected QT (QTc) prolongation displayed peaks at 2.5 and 60 minutes after a supratherapeutic dose. The mean plasma concentration peaked at 5 minutes, declining rapidly thereafter. OBJECTIVE: The purpose of this study was to examine the basis for the delayed effect of oliceridine to prolong the QTc interval. METHODS: Repolarization parameters and tissue accumulation of oliceridine were evaluated in rabbit left ventricular wedge preparations over a period of 5 hours. The effects of oliceridine on ion channel currents were evaluated in human embryonic kidney and Chinese hamster ovary cells. Quinidine was used as a control. RESULTS: Oliceridine and quinidine produced a progressive prolongation of the QTc interval and action potential duration over a period of 5 hours, paralleling slow progressive tissue uptake of the drugs. Oliceridine caused modest prolongation of these parameters, whereas quinidine produced a prominent prolongation of action potential duration and QTc interval as well as development of early afterdepolarization (after 2 hours), resulting in a high torsades de pointes score. The 50% inhibitory concentration values for the oliceridine inhibition of the rapidly activating delayed rectifier current (human ether a-go-go current) and late sodium channel current were 2.2 and 3.45 µM when assessed after traditional acute exposure but much lower after 3 hours of drug exposure. CONCLUSION: Our findings suggest that a gradual increase of intracellular access of drugs to the hERG channels as a result of their intracellular uptake and accumulation can significantly delay effects on repolarization, thus confounding the assessment of QT interval prolongation and arrhythmic risk when studied acutely. The multi-ion channel effects of oliceridine, late sodium channel current inhibition in particular, point to a low risk of devloping torsades de pointes.
Assuntos
Arritmias Cardíacas , Canal de Potássio ERG1/antagonistas & inibidores , Compostos de Espiro/farmacocinética , Tiofenos/farmacocinética , Analgésicos Opioides/farmacocinética , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/prevenção & controle , Linhagem Celular , Cricetulus , Humanos , Concentração Inibidora 50 , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/metabolismo , Síndrome do QT Longo/fisiopatologia , Moduladores de Transporte de Membrana/farmacologia , Quinidina/farmacocinética , Distribuição Tecidual , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinéticaRESUMO
Apelin, a ligand of the G protein-coupled putative angiotensin II-like receptor (APJ-R), exerts strong vasodilating, cardiac inotropic and chronotropic actions. Its expression is highly up-regulated during heart failure. Apelin also increases cardiac conduction speed and excitability. While our knowledge of apelin cardiovascular actions is growing, our understanding of the physiological mechanisms behind the cardiac effects remains limited. We tested the effects of apelin on the cardiac sodium current (I(Na)) using patch clamp technique on cardiac myocytes acutely dissociated from dog ventricle. We found that apelin-13 and apelin-17 increased peak I(Na) by 39% and 61% and shifted its mid-activation potential by -6.8+/-0.6 mV and -17+/-1 mV respectively thus increasing channel opening at negative voltage. Apelin also slowed I(Na) recovery from inactivation. The effects of apelin on I(Na) amplitude were linked to activation of protein kinase C. Apelin also increased I(Na) "window" current by up to 600% suggesting that changes in intracellular sodium may contribute to the apelin inotropic effects. Our results reveal for the first time the effects of apelin on I(Na). These effects are likely to modulate cardiac conduction and excitability and may have beneficial antiarrhythmic action in sodium chanelopathies such as Brugada Syndrome where I(Na) amplitude is reduced.
Assuntos
Proteínas de Transporte/farmacologia , Miocárdio/metabolismo , Sódio/química , Potenciais de Ação , Animais , Apelina , Cães , Eletrofisiologia/métodos , Coração/fisiologia , Humanos , Imuno-Histoquímica/métodos , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Técnicas de Patch-Clamp , Pericárdio/metabolismo , Ratos , Canais de Sódio/químicaRESUMO
Recent development of drugs for the treatment of atrial fibrillation (AF) has focused on atrial selective agents. We examined the atrioventricular differences in sodium channel block of the antiarrhythmic agent AZD1305 in atria and ventricles of anesthetized dogs in vivo, canine isolated arterially perfused preparations in vitro, and isolated myocytes using whole-cell patch-clamp techniques. AZD1305 did not change heart rate or blood pressure in vivo but prolonged action potential duration and increased effective refractory period, diastolic threshold of excitation, and conduction time preferentially in atria both in vitro and in vivo. AZD1305 reduced the maximum rate of rise of the action potential upstroke (V(max)) predominantly in atria (-51% +/- 10% in atria vs. -31% +/- 23% in ventricles; 3 microM; cycle length = 500 milliseconds). Fast sodium current (I(Na)) was blocked by AZD1305 to a greater degree in atrial versus ventricular myocytes (particularly tonic inhibition). In coronary-perfused right atria, AZD1305 very effectively prevented induction of persistent acetylcholine-mediated AF and, in a different set of atria, terminated persistent AF (in 5 of 5 and 7 of 8 atria, respectively). In conclusion, AZD1305 exerts atrial predominant sodium channel-blocking effects in vitro and in vivo and effectively suppresses AF.
Assuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/tratamento farmacológico , Compostos Azabicíclicos/farmacologia , Carbamatos/farmacologia , Acetilcolina , Potenciais de Ação/efeitos dos fármacos , Animais , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Cães , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Feminino , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Sódio/farmacologiaRESUMO
BACKGROUND: J wave syndromes (JWS), including Brugada (BrS) and early repolarization syndromes (ERS), are associated with increased risk for life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently very limited. Here, we evaluate the effects of the natural flavone acacetin. METHODS: The effects of acacetin on action potential (AP) morphology and transient outward current (Ito) were first studied in isolated canine RV epicardial myocytes using whole-cell patch clamp techniques. Acacetin's effects on transmembrane APs, unipolar electrograms and transmural ECGs were then studied in isolated coronary-perfused canine RV and LV wedge preparations as well as in whole-heart, Langendorff-perfused preparations from which we recorded a 12 lead ECG and unipolar electrograms. Using floating glass microelectrodes we also recorded transmembrane APs from the RVOT of the whole-heart model. The Ito agonist NS5806, sodium channel blocker ajmaline, calcium channel blocker verapamil or hypothermia (32°C) were used to pharmacologically mimic the genetic defects and conditions associated with JWS, thus eliciting prominent J waves and provoking VT/VF. RESULTS: Acacetin (5-10 µM) reduced Ito density, AP notch and J wave area and totally suppressed the electrocardiographic and arrhythmic manifestation of both BrS and ERS, regardless of the experimental model used. In wedge and whole-heart models of JWS, increasing Ito with NS5806, decreasing INa or ICa (with ajmaline or verapamil) or hypothermia all resulted in accentuation of epicardial AP notch and ECG J waves, resulting in characteristic BrS and ERS phenotypes. Phase 2-reentrant extrasystoles originating from the RVOT triggered VT/VF. The J waves in leads V1 and V2 were never associated with a delay of RVOT activation and always coincided with the appearance of the AP notch recorded from RVOT epicardium. All repolarization defects giving rise to VT/VF in the BrS and ERS models were reversed by acacetin, resulting in total suppression of VT/VF. CONCLUSIONS: We present experimental models of BrS and ERS capable of recapitulating all of the ECG and arrhythmic manifestations of the JWS. Our findings provide definitive support for the repolarization but not the depolarization hypothesis proposed to underlie BrS and point to acacetin as a promising new pharmacologic treatment for JWS.
Assuntos
Síndrome de Brugada , Eletrocardiografia , Flavonas/farmacologia , Miócitos Cardíacos/metabolismo , Pericárdio/metabolismo , Ajmalina/farmacologia , Animais , Síndrome de Brugada/induzido quimicamente , Síndrome de Brugada/tratamento farmacológico , Síndrome de Brugada/metabolismo , Síndrome de Brugada/fisiopatologia , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Humanos , Hipotermia/metabolismo , Hipotermia/patologia , Hipotermia/fisiopatologia , Compostos de Fenilureia/farmacologia , Tetrazóis/farmacologia , Verapamil/farmacologiaRESUMO
The pharmacological approach to therapy of atrial fibrillation (AF) is often associated with adverse effects resulting in the development of ventricular arrhythmias. As a consequence, much of the focus in recent years has been on development of atrial-selective agents. Atrial-selective sodium channel blockers have recently been shown to exist and be useful in the management of AF. This review summarizes the available data relative to current therapies, focusing on our understanding of the actions of atrial selective sodium channel blockers in suppressing and preventing the induction of AF and electrophysiological properties that confer atrial-selectivity to these antifibrillatory drugs.
Assuntos
Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Átrios do Coração/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores dos Canais de Sódio/uso terapêutico , Animais , Fibrilação Atrial/fisiopatologia , Sistemas de Liberação de Medicamentos , Átrios do Coração/fisiopatologia , Humanos , Estrutura MolecularRESUMO
Atrial fibrillation (AF) is a growing clinical problem, increasing in prevalence as the population of the United States and countries around the world ages. Intensive research aimed at improving prevention, diagnosis, and treatment of AF is ongoing. Although the use and efficacy of catheter ablation-based approaches in AF treatment have increased significantly in the last decade, pharmacological agents remain the first-line therapy for rhythm management of AF. Currently available anti-AF agents are generally only moderately effective and associated with extracardiac toxicity and/or a risk for development of life-threatening ventricular arrhythmias. Included among current investigational strategies for improving the effectiveness and safety of anti-AF drugs is the development of (1) Agents that produce atrial-specific or predominant inhibition of I(Kur), I(K-ACh), or I(Na); (2) "Upstream therapies" that effect nonion channel targets that reduce atrial structural remodeling, hypertrophy, dilatation, inflammation, oxidative injury, etc; (3) Derivatives of "old" anti-AF drugs with an improved safety pharmacological profile; and (4) Gap junction therapy aimed at improving conduction without affecting sodium channels. This review focuses on new pharmacological approaches under investigation for the treatment of AF.