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...