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1.
Cardiovasc Res ; 98(1): 136-44, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23341577

RESUMO

AIMS: Na(+) channel blockers are often used to treat atrial fibrillation (AF), but may sometimes cause ventricular contractile dysfunction. However, amiodarone, a multi-channel blocker with Na(+) channel block, causes less contractile dysfunction. In this study, we tested the hypothesis that Na(+) channel block by amiodarone is selective in atrial myocytes (AM) compared with ventricular myocytes (VM). METHODS AND RESULTS: Na(+) currents (INa) were measured using whole-cell patch-clamp technique in isolated rabbit AM and VM. Amiodarone inhibited INa in AM (IC50: 1.8 ± 1.1 µM; n = 8) much more than in VM (40.4 ± 11.9 µM; n = 7, P < 0.01). Amiodarone at 10 µM shifted the steady-state inactivation relationship in AM (-16.2 ± 1.7 mV shift, n = 12) compared with VM (-5.9 ± 0.7 mV shift; n = 13; P < 0.01). For mexiletine, the inhibition of INa and inactivation curve shifts were comparable for AM and VM. The effects of amiodarone and mexiletine on conduction velocity (CV) in Langendorff-perfused rabbit hearts were evaluated using an optical mapping system. The decrease of CV by 3 µM amiodarone was significantly larger in the atrium (-18.9 ± 3.8% change; n = 5) compared with the ventricle (-3.7 ± 3.7%; n = 5; P < 0.01). In contrast, mexiletine reduced CV equally in the atrium and the ventricle. CONCLUSION: Amiodarone preferentially inhibits INa of AM compared with VM. Atrial selective Na(+) channel block by amiodarone may contribute to treating AF with less effect on ventricular contractility than other Na(+) channel blockers.


Assuntos
Amiodarona/farmacologia , Átrios do Coração/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Sistema de Condução Cardíaco/efeitos dos fármacos , Sistema de Condução Cardíaco/fisiologia , Masculino , Mexiletina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Coelhos
2.
Heart Rhythm ; 6(5): 684-92, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19303369

RESUMO

BACKGROUND: Modification of spiral wave (SW) reentry by antiarrhythmic drugs is a central issue to be challenged for better understanding of their benefits and risks. OBJECTIVE: We investigated the effects of pilsicainide and/or verapamil, which block sodium and L-type calcium currents (I(Na) and I(Ca,L)), respectively, on SW reentry. METHODS: A two-dimensional epicardial ventricular muscle layer was created in rabbit hearts by cryoablation (n = 32), and action potential signals were analyzed by high-resolution optical mapping. RESULTS: During constant stimulation, pilsicainide (3-5 microM) caused a frequency-dependent decrease of conduction velocity (CV; by 20%-54% at 5 Hz) without affecting action potential duration (APD). Verapamil (3 microM) caused APD shortening (by 16% at 5 Hz) without affecting CV. Ventricular tachycardias (VTs) that were induced were more sustained in the presence of either pilsicainide or verapamil. The incidence of sustained VTs (>30 s)/all VTs per heart was 58% +/- 9% for 5 microM pilsicainide vs. 22% +/- 9% for controls and 62% +/- 10% for 3 microM verapamil vs. 22% +/- 8% for controls. The SWs with pilsicainide were characterized by slower rotation around longer functional block lines (FBLs), whereas those with verapamil were characterized by faster rotation around shorter FBLs. Combined application of 3 microM pilsicainide and 3 microM verapamil resulted in early termination of VTs (sustained VTs/all VTs per heart: 2% +/- 2% vs. 29% +/- 9% for controls); SWs showed extensive drift and decremental conduction, leading to their spontaneous annihilation. CONCLUSION: Blockade of either I(Na) or I(Ca,L) stabilizes SWs in a two-dimensional epicardial layer of rabbit ventricular myocardium to help their persistence, whereas blockade of both currents destabilizes SWs to facilitate their termination.


Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo L/efeitos dos fármacos , Ventrículos do Coração/patologia , Lidocaína/análogos & derivados , Bloqueadores dos Canais de Sódio/uso terapêutico , Taquicardia por Reentrada no Nó Sinoatrial/tratamento farmacológico , Verapamil/uso terapêutico , Animais , Modelos Animais de Doenças , Técnicas Eletrofisiológicas Cardíacas , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Lidocaína/uso terapêutico , Pericárdio/patologia , Coelhos , Canais de Sódio/efeitos dos fármacos , Canais de Sódio/metabolismo , Taquicardia por Reentrada no Nó Sinoatrial/metabolismo , Taquicardia por Reentrada no Nó Sinoatrial/patologia , Resultado do Tratamento
3.
J Pharmacol Sci ; 108(3): 301-7, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18987434

RESUMO

Block of cardiac hERG K+ channels by the antihistamine terfenadine and the prokinetic agent cisapride is associated with prolonged ventricular repolarization and an increased risk of ventricular arrhythmia. Here, we used a site-directed mutagenesis approach to determine the molecular determinants of hERG block by terfenadine and cisapride. Wild-type and mutant hERG channels were heterologously expressed in Xenopus laevis oocytes and characterized by measuring whole cell currents with two-microelectrode voltage clamp techniques. Mutation of T623, S624, Y652, or F656 to Ala reduced channel sensitivity to block by terfenadine. The same mutations reduced sensitivity to cisapride. These data confirm our previous findings that polar residues (T623, S624) located near the base of the pore helix and aromatic residues (Y652, F656) located in the S6 domain are key molecular determinants of the hERG drug binding site. Unlike methanesulfonanilides (dofetilide, MK-499, E-4031, ibutilide) or clofilium, mutation of V625, G648, or V659 did not alter the sensitivity of hERG channels to terfenadine or cisapride. As previously proposed by molecular modeling studies (Farid R, et al. Bioorg Med Chem. 2006;14:3160-3173), our findings suggest that different drugs can adopt distinct modes of binding to the central cavity of hERG.


Assuntos
Cisaprida/farmacologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Terfenadina/farmacologia , Animais , Sítios de Ligação , Cisaprida/metabolismo , Relação Dose-Resposta a Droga , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/química , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/metabolismo , Fármacos Gastrointestinais/farmacologia , Técnicas de Transferência de Genes , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacologia , Humanos , Potenciais da Membrana , Mutagênese , Bloqueadores dos Canais de Potássio/metabolismo , Conformação Proteica , Terfenadina/metabolismo , Fatores de Tempo , Xenopus laevis
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