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Effects of Tedisamil (KC8857) on Cardiac Electrophysiology And

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Effects of Tedisamil (KC8857) on Cardiac Electrophysiology And Bridsh Joumal of Phamacology (1996) 117, 1261 1269 Bl 1996 Stockton Press All rights reserved 0007-1188/96 $12.00 M Effects of tedisamil (KC-8857) on cardiac electrophysiology and ventricular fibrillation in the rabbit isolated heart Liguo Chi, James L. Park, Gregory S. Friedrichs, Yasmin A. Banglawala, Maria A. Perez, Elaine J. Tanhehco & 'Benedict R. Lucchesi Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0632, U.S.A. 1 The direct cardiac electrophysiological and antifibrillatory actions of tedisamil (KC-8857) were studied in rabbit isolated hearts. 2 Tedisamil (1, 3, and 10 gM), prolonged the ventricular effective refractory period (VRP) from 120±18 ms (baseline) to 155 + 19, 171+20, and 205+14 ms, respectively. Three groups of isolated hearts (n = 6 each) were used to test the antifibrillatory action of tedisamil. Hearts were perfused with 1.25 Mm pinacidil, a KATP channel activator. Hearts were subjected to hypoxia for 12 min followed by 40 min of reoxygenation. Ventricular fibrillation (VF) developed during hypoxia and reoxygenation in both the control and 1 gM tedisamil-treated groups (5/6 and 4/6, respectively). Tedisamil (3 gM) reduced the incidence of VF (0/6, P= 0.007 vs. control). 3 In a separate group of hearts, VF was initiated by electrical stimulation. The administration of 0.3 ml of 10 mM tedisamil, via the aortic cannula, terminated VF in all hearts, converting them to normal sinus rhythm. 4 Tedisamil (3 gM) reversed pinacidil-induced negative inotropic effects in rabbit isolated atrial muscle which were equilibrated under normoxia, as well as in atrial muscle subjected to hypoxia and reoxygenation. 5 The results demonstrate a direct antifibrillatory action of tedisamil in vitro. The mechanism responsible for the observed effects may involve modulation by tedisamil of the cardiac ATP-regulated potassium channel, in addition to its antagonism of IK and Ith. Keywords: Class III antiarrhythmics; arrhythmia; KATp-regulated channel blocker; chemical defibrillation; myocardial ischaemia; potassium currents Introduction In experimental studies and clinical trials, Class III antiar- isolated ventricular mycocytes, tedisamil, at low concentra- rhythmic agents have been demonstrated to be more effective tions (1-20 gM), selectively suppressed IO and prolonged ac- than other classes of antiarrhythmic drugs in preventing lethal tion potential duration (Dukes & Morad, 1989; Dukes et al., ventricular arrhythmias (Lynch et al., 1992; Lucchesi et al., 1990). Tedisamil had no significant effects on the inward rec- 1993; Gilman et al., 1994). By prolonging the ventricular ef- tifier K+ current, or inward Ca2" current in rat or guinea-pig fective refractory period and action potential duration, Class ventricular myocytes and blocked the Na' current only at III antiarrhythmic agents abolish re-entrant impulses and concentrations above 20 uM (Dukes & Morad, 1989; Dukes et prevent or terminate ventricular fibrillation (Sanguinetti, 1992; al., 1990). In both conscious and anaesthetized rats, tedisamil Uprichard & Lucchesi, 1994). Currently available Class III (i.v.) lengthened the ventricular effective refractory period, drugs (amiodarone and sotalol) not only block K+ currents in action potential duration, QT interval, and reduced the in- the heart, but also act on other ion channels and/or receptors cidence of ventricular fibrillation induced by coronary artery causing unwanted effects (Sanguinetti, 1992). Recently devel- ligation. In addition, tedisamil caused bradycardia and in- oped Class III antiarrhymthmic agents, such as sematilide, creased systemic blood pressure (Howard et al., 1989; Beatch MS-551, E-4031, and dofetilide (UK 68,798), selectively block et al., 1990; 1991). The antifibrillatory effects and associated the delayed rectifier K+ current (IK), but the reverse use- electrophysiological actions oftedisamil have been examined in dependence properties of these agents could limit their ther- vivo (Beatch et al., 1990; 1991) as well as in rat isolated hearts apeutic utilily (Hondeghem & Snyders, 1990; Baskin et al., (Tsuchihashi & Curtis, 1991), a species in which I,, is the 1991; Nakaya et al., 1993; Sager et al., 1993). Thus, the search predominant repolarization current (Josephson et al., 1984; for new compounds in this class as well as compounds tar- Dukes & Morad, 1989). geting other types of K+ channels remains an important area The present study explores the electrophysiological prop- of investigation. erties of tedisamil, and more importantly, demonstrates the Recent studies have shown that blockade of the transient antifibrillatory effects of tedisamil in a species possessing both outward current (Ito) and inward rectifier K+ current (I , both functional Ito and IK in the ventricular myocardium (Giles & of which are involved in the repolarization of the action po- Imiazumi 1988; Hiraoka & Kawano, 1989; Carmeliet, 1993; de tential (Carmeliet, 1992a), contribute to antiarrhythmic and Lorenzi et al., 1994). We used the rabbit isolated heart model antifibrillatory actions (Beatch et al., 1991; Rees & Curtis, in the present study to determine the direct, concentration- 1993). Tedisamil (KC-8857; 3,7-di-(cyclopropyhmethyl)-9, 9- dependent effects of tedisamil on the ventricular effective re- tetramethylene-3, 7-diazabicyclo [3.3.1]-nonanedihydrochlor- fractory period and atrioventricular node conduction because, ide) is a bradycardic agent and a putative Ito blocker. In rat like the rat, the rabbit myocardium contains prominent, functional I,, and IKE In addition, the effects of tedisamil were examined in two models: prevention of hypoxia/reoxygena- tion/pinacidil-induced ventricular fibrillation and reversal of 'Author for correspondence. electrically-induced ventricular fibrillation. 1262 L. Chi et al Effects of tedisamil in vitro Methods wave' of the electrogram. The excitation threshold voltage was defined as the minimum voltage required to elicit a propagated The studies were performed in accordance with the guidelines ventricular impulse. The refractory period determined in the of the 'University of Michigan Committee on the Use and Care region of RVOT is defined as the longest R-wave to S2 stimulus of Animals'. The animal care and use programme conforms to interval that failed to elicit a propagated ventricular complex the standards in 'The Guide for the Care and Use of La- at 1.5 times threshold voltage. The P- R interval was de- boratory Animals', DHEW Publ. No. (NIH) 86-23. termined from the electrogram recording. After a 60 min period of equilibration, the hearts were perfused with buffer Langendorif perfused isolated heart preparation containing 0.1, 1, 3 or 10 iM tedisamil. Electrophysiological parameters were determined 15 min after exposure to each New Zealand white rabbits (2.1-2.5 kg) were randomized to concentration of tedisamil. Figure la illustrates the experi- different experimental groups. All rabbits were killed by cer- mental protocol. vical dislocation. The hearts were removed rapidly and pre- pared for perfusion by the Langendorff method using a Protocol 2: Hypoxia/reoxygenation and pinacidil-induced ven- modified Krebs-Henseleit buffer. Coronary artery perfusion tricular fibrillation (Figure 1) A total of 22 rabbit isolated was maintained with the use of a roller pump adjusted to hearts were used in this portion of the experiment, from which produce a mean coronary artery perfusion pressure of 4 hearts were excluded before entering the protocol due to 40 + 5 mmHg (20 +2 ml min-') maintained throughout the technical failures. Eighteen hearts were randomly allocated to experimental protocol. The hearts were paced at a frequency of three experimental groups: control, n = 6; tedisamil (1 tUM), 10-20% above their intrinsic sinoatrial rate. The pacing sti- n = 6; tedisamil (3 gM), n = 6. After 30 to 40 min of equilibra- mulus was provided by a Grass SD5 (Grass Instrument tion, the isolated hearts were perfused with buffer containing Company, Quincy, MA, U.S.A.) pulse generator and applied drug-vehicle solution (control) or tedisamil (1 gM and 3 MM) to the right atrium via bipolar electrodes. The pacing stimulus for 10 min followed by pinacidil (1.25 AM), an ATP-regulated was set at 10% above threshold voltage and a pulse duration of K+ (KATP) channel opener, added to the buffer. Five min after 4 ms. A cannula with a latex balloon at its distal end was the addition ofpinacidil, the hearts were subjected to 12 min of inserted through the left atrium, across the mitral valve and perfusion under hypoxic conditions by changing the gas mix- placed in the left ventricle. The proximal end of the cannula ture in the 'artificial lung' to 95%N2/5%CO2. At the end of the was connected to a pressure transducer for recording left hypoxic perfusion period, normoxic perfusion of the heart was ventricular systolic and end-diastolic pressures. The balloon reinstituted (reoxygenation) and maintained for 40 min. The was expanded with distilled water to establish a ventricular cardiac electrogram, coronary perfusion pressure and left end-diastolic pressure of 5 mmHg. The volume in the in- ventricular function were monitored continuously. The end- traventricular balloon was maintained constant throughout point of the experiment was defined as the occurrence of sus- the course of each experiment. A polyethylene cannula was tained ventricular fibrillation during hypoxia and/or reox- placed in the left ventricle to vent the chamber. A thermistor ygenation. The composition of the buffer perfusate in this probe (Tele-thermometer, Yellow Springs Instrument Co. protocol had the following composition (in mmol I`): NaCl Yellow Springs, OH, U.S.A.) was inserted in the left ventricle 117, KCl 1.4, CaCl2.H20 2.4, MgCl2.6H20 1.2, NaHCO3 25, to monitor the temperature of the heart. The electrogram was KH2PO4 1.1, glucose 5.0, monosodium L-glutamate 5.0 and recorded by electrodes attached to the aorta and apex of the sodium pyruvate 2.0. The final concentration of K+ in the heart. A pressure transducer was connected to a side arm of the perfusion medium was 2.5 mM. aortic cannula to monitor the coronary artery perfusion pressure (CPP).
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