Combined Effects of Nifekalant and Lidocaine on the Spiral-Type Re-Entry in a Perfused 2-Dimensional Layer of Rabbit Ventricular Myocardium

Abstract

piral-type excitation is the principal mechanism of functional re-entry for the genesis of life-threatening ventricular tachycardia and ventricular fibrillation (VT/VF). 1,2 Nifekalant (NIF) hydrochloride is a new class III antiarrhythmic drug developed in Japan that causes dose-dependent prolongation of action potential duration (APD) in both atrial and ventricular muscle, mainly by reducing the rapid component of the delayed rectifier potassium current (IKr). [3][4][5][6][7] The 2000 American Heart Association Guidelines for cardiopulmonary resuscitation (CPR) recommends intravenous amiodarone to prevent recurrent VT/VF, 8,9 but amiodarone has not yet been approved for CPR in Japan and intravenous NIF is used, often in combination with lidocaine (LID), as an alternative. 10 Nifekakant and LID are also used sequentially to treat recurrent VT/VF resistant to DC shocks; 11-13 however, little information is available on the electropharmacological basis for the combined use of these drugs. The present study was designed to investigate the effects of NIF and NIF + LID on the spiral-type excitation in a perfused 2-dimensional (D) layer of rabbit ventricle by using our custom-made high-resolution optical mapping system. Methods Experimental ModelJapanese White rabbits of both sexes weighing 1.7-2.0 kg (n=13) were anesthetized with thiamylal sodium (10-15 mg/kg), and after opening the thorax, the heart was rapidly removed. Complete atrioventricular block was produced by ligating the His bundle with fine silk thread. The aorta was then cannulated, and the heart was connected to a Langendorff perfusion apparatus. The coronary arteries were perfused with modified Krebs Ringer solution at a constant flow (35-45 ml/min). The solution was equilibrated with 95% O2 and 5% CO2 to maintain its pH at 7.4, and its temperature was maintained at 35°C.Because of its 3-D structure with variable filament configuration, vortex-type excitations appear only transiently and incidentally in the intact heart, 14 thereby hampering detailed analysis of spiral dynamics by optical mapping. To avoid this problem, we created a 2-D preparation by the method described by Schalij et al. 15 In brief, the Langendorff-perfused rabbit heart was immersed in a tissue bath containing perfusion fluid at 35°C, and a cryoprobe made of copper was inserted into the left ventricular cavity, and the probe was then filled with liquid nitrogen (-192°C) for 5 min. This freezing procedure destroyed the endocardial and intramural layers of the free wall of the left ventricle and the total interventricular septum, leaving only Background Spiral re-entry plays the principal role in the genesis of ventricular tachycardia and ventricular fibrillation (VT/VF). The specific IKr blocker, nifekakant (NIF) has, often in combination with lidocaine (LID), recently been used in Japan to prevent recurrent VT/VF, but the combined effects of these drugs on spiral reentry had never been investigated. Methods and ResultsA ventricular epicardial sheet was obtained from 13 Langendorff-pe...

Nifekalant Hydrochloride Administration During Cardiopulmonary Resuscitation Improves the Transmural Dispersion of Myocardial Repolarization Experimental Study in a Canine Model of Cardiopulmonary Arrest

“…3 Recently, our coworkers Amino et al conducted a comparative investigation of the 90% APD (APD90) prolonging effect of NIF on the surface of the left ventricle (LV) and APD90 dispersion (APDD) in isolated perfused rabbit hearts at basic cycle lengths (BCLs) of 400 ms and 250 ms. APD90 was prolonged with the efficacy of a reverse use dependent block without increasing the APDD at either BCL, and as a result NIF decreased VT/VF vulnerability. 4 These study results suggest that NIF may stop VT/VF by improving epicardial surface and transmural dispersion of repolarization (TDR) in the LV, in addition to its refractory-period-prolonging action.In a clinical study, we used NIF to treat lidocaine-resistant VT/VF in patients with out-of-hospital cardiopulmonary arrest (OHCPA), and reported that it exerted excellent anti-arrhythmic efficacy. 5 In a study in which we compared OHCPA patients with acidosis and in-hospital cardiopulmonary arrest (IHCPA) patients without acidosis, NIF was Background Because nifekalant hydrochloride (NIF) displayed a superior defibrillating effect on ventricular tachycardia/fibrillation (VT/VF) in cardiopulmonary arrest (CPA) patients, despite some QT prolongation, its effect on transmural dispersion of repolarization (TDR) in the left ventricle (LV) in an animal model of CPA was investigated.…”

“…3 Recently, our coworkers Amino et al conducted a comparative investigation of the 90% APD (APD90) prolonging effect of NIF on the surface of the left ventricle (LV) and APD90 dispersion (APDD) in isolated perfused rabbit hearts at basic cycle lengths (BCLs) of 400 ms and 250 ms. APD90 was prolonged with the efficacy of a reverse use dependent block without increasing the APDD at either BCL, and as a result NIF decreased VT/VF vulnerability. 4 These study results suggest that NIF may stop VT/VF by improving epicardial surface and transmural dispersion of repolarization (TDR) in the LV, in addition to its refractory-period-prolonging action.…”

Altered expression of connexin43 contributes to the arrhythmogenic substrate during the development of heart failure in cardiomyopathic hamster

“…We used a high-resolution optical mapping system to examine the electrophysiological properties of the heart. Details of the system and mapping procedure were described in our previous studies (2,42). In brief, isolated hamster hearts were continuously perfused on a Langendorff apparatus with modified Krebs-Ringer solution equilibrated with 95% O 2-5% CO2 (37°C, pH 7.4).…”

Can Nifekalant Hydrochloride be Used as a First-Line Drug for Cardiopulmonary Arrest (CPA)?

“…In a preliminary study, Amino et al investigated the effects of combined NIF and LID administration on the functions of the left ventricle in rabbit hearts using an optical mapping system, and found that the pharmacological actions of NIF (0.5 mol/L) on the spiral excitations of the left ventricle were reversed by LID (3 mol/L). 31 The APD prolongation caused by NIF was readily countered by the concomitant reduction of INa, slow in response to LID; thus, the vulnerability to VF was significantly increased in the presence of both NIF and LID as compared with that in the presence of NIF alone. From also these reasons, LID administration after NIF or concurrent use of LID plus NIF is not recommended.…”