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Comparison of Electropharmacological Effects of Bepridil and Sotalol in Halothane-Anesthetized Dogs

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Comparison of Electropharmacological Effects of Bepridil and Sotalol in Halothane-Anesthetized Dogs Circ J 2008; 72: 1003–1011 Comparison of Electropharmacological Effects of Bepridil and Sotalol in Halothane-Anesthetized Dogs Tomomichi Ishizaka, DVM*,**; Akira Takahara, PhD*; Hiroshi Iwasaki, MD*; Yoshitaka Mitsumori, MD*; Hiroaki Kise, MD*; Yuji Nakamura, MS*; Atsushi Sugiyama, MD*,** Background Bepridil is known to have a multiple ion channel-blocking property in the heart, which has been applied for the treatment of atrial fibrillation and drug-refractory ventricular tachyarrhythmias. In this study, the electro-pharmacological effects of bepridil were compared with those of dl-sotalol, a representative class III anti- arrhythmic drug, using the halothane-anesthetized canine model. Methods and Results Cardiovascular and electrophysiological variables were measured under the halothane anesthesia. Intravenous administration of bepridil (0.3mg/kg, n=4) delayed the intraventricular conduction and prolonged the ventricular effective refractory period, whereas dl-sotalol (0.3mg/kg, iv, n=4) inhibited atrioven- tricular conduction and prolonged the atrial and ventricular effective refractory period. The additional adminis- tration of 10 times the higher dose of bepridil or dl-sotalol (ie, 3mg/kg, iv, n=4 for each group) decreased blood pressure, suppressed ventricular contraction and sinus automaticity, and prolonged the atrial and ventricular effective refractory period and monophasic action potential duration, in addition to the effects of the low dose. Conclusions The electropharmacological effects of bepridil and dl-sotalol were similar, although their potency for each cardiovascular variable varied significantly. These findings can be useful when selecting these drugs according to the pathophysiological condition of a patient. (Circ J 2008; 72: 1003–1011) Key Words: Bepridil; Electrophysiological effects; Hemodynamics; dl-Sotalol epridil was initially introduced as an anti-anginal (β-adrenoceptor and IKr blocker) in terms of negative drug possessing a Ca2+ channel-blocking proper- chronotropic, inotropic and dromotropic actions, as well as B ty.1,2 The drug has been shown to also inhibit the effects on atrial and ventricular refractoriness.17,18 To clarify cardiac Na+ and K+ channels, which can prolong the atrial any similarity and differences in the cardiovascular pharma- and ventricular effective refractory periods.3–6 Recent clini- cological profile between the 2 drugs, in the present study we cal studies in Japan demonstrated that bepridil is efficacious precisely assessed the in vivo effects of bepridil in compari- against atrial fibrillation or drug-refractory ventricular son with a representative class III antiarrhythmic, drug dl- tachyarrhythmias.7–11 In vitro electrophysiological studies sotalol, on the cardiac repolarization process, together with have indicated that bepridil can block various types of K+ multiple cardiohemodynamic and electrophysiological vari- channels, including a rapid component of delayed rectifier ables. We used the halothane-anesthetized canine model in K+ currents (IKr),6 ultra-rapid component of delayed rectifier this study, which is useful in simultaneously analyzing in K+ current (IKur),12 slow component of delayed rectifier K+ vivo cardiovascular and electrophysiological profiles of current (IKs),6 transient outward current (Ito),13 inward recti- various drugs.19–24 fier K+ current (IK1) and muscarinic acetylcholine receptor- operated K+ current (IK,ACh).14 The in vivo cardiovascular and electrophysiological Methods profile of bepridil has been analyzed in comparison with Animals were obtained through the Animal Laboratory classical Ca2+ channel blockers such as verapamil and for Research, University of Yamanashi. All experiments diltiazem,15,16 because bepridil belongs to class IV anti- were performed according to the Guidelines for Animal arrhythmics. However, the pharmacological profile is con- Experiments, University of Yamanashi. Eight beagle dogs of sidered to be fundamentally similar to that of dl-sotalol either sex, weighing approximately 10kg, were divided into 2 animal groups: bepridil group (n=4) or dl-sotalol group (n=4). Dogs were initially anesthetized with thiopental (Received September 5, 2007; revised manuscript received December 19, 2007; accepted January 7, 2008) sodium (30mg/kg, iv). After intubation with a cuffed endo- *Department of Pharmacology, Interdisciplinary Graduate School tracheal tube, 1% halothane vaporized with 100% oxygen of Medicine and Engineering, University of Yamanashi, Chuo, was inhaled with a volume-limited ventilator (SN-408-3; **Yamanashi Research Center of Clinical Pharmacology, Fuefuki, Shinano, Tokyo, Japan). Tidal volume and respiratory rate Japan were set at 20ml/kg and 15strokes/min, respectively. Mailing address: Atsushi Sugiyama, MD, Department of Pharmacol- ogy, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo 409-3898, Japan. Measurement of Cardiohemodynamic Parameters E-mail: [email protected] A heparinized catheter was inserted through the right All rights are reserved to the Japanese Circulation Society. For per- femoral artery for continuous monitoring of the systemic missions, please e-mail: [email protected] blood pressure. A thermodilution catheter (TC-704; Nihon- Circulation Journal Vol.72, June 2008 1004 ISHIZAKA T et al. Kohden, Tokyo, Japan) was positioned at the right side of stimulus of various coupling intervals. The duration of the the heart via the right femoral vein. The cardiac output was terminal repolarization period of the ventricle was calcu- measured by the standard thermodilution method, using a lated by the difference between the MAP90(CL400) and the cardiac output computer (MFC-1100; Nihon-Kohden). effective refractory period at the same site, which reflects Total peripheral vascular resistance was calculated using the extent of the electrical vulnerability of the ventricular the basic equation: Mean blood pressure/Cardiac output. A muscle.27 pig-tail catheter was positioned at the left ventricle through the right femoral artery to measure the left ventricular pres- Experimental Protocol sure (LVP). The maximal upstroke velocity of the LVP (ie, The cardiohemodynamic and electrophysiological param- LVdP/dtmax) and left ventricular end-diastolic pressure eters were monitored continuously using a polygraph sys- (LVEDP) were recorded during the sinus rhythm to estimate tem (RM-6000; Nihon-Kohden) and recorded on a thermal the contractility and preload of the left ventricle, respec- array recorder (WS-682G; Nihon-Kohden). These parameters tively. were analyzed using a real-time full automatic data analysis system (MP/VAS 3 for Macintosh ver.1.0; Physio-Tech, Measurement of Electrophysiologic Parameters Tokyo, Japan). Each measurement of the electrocardiogram, The surface lead II electrocardiogram was obtained from monophasic action potential signals, atrio-His and His-ven- the limb electrodes. Corrected QT intervals (QTc) were cal- tricular intervals was the mean of 3 recordings of consecu- culated using Bazett’s formula25 [QTc(B)=QT/(60/heart tive recordings. The cardiovascular variables were assessed rate)1/2], and Van de Water’s formula26 [QTc(V)=QT–87 in the following order at each dose. The electrocardiogram, (60/heart rate–1)], whereby a unit is given in seconds. A His-bundle electrogram, systemic and LVP, and monopha- quad-polar electrodes catheter was positioned at the non- sic action potential signals were recorded under the sinus coronary cusp of the aortic valves through the left femoral rhythm. The cardiac output was measured twice. The mono- artery to obtain the His-bundle electrogram. Another quad- phasic action potential signals were recorded during the polar electrodes catheter was positioned at the high right ventricle pacing at a cycle length of 400 and 300ms. The atrium through the right femoral vein for electrically pacing sinus node recovery time was assessed twice. Finally, the the right atrium. A bi-directional steerable monophasic Wenckebach block pacing cycle length, functional refrac- action potential recording/pacing combination catheter tory period of the atrioventricular node, and effective (1675P; EP Technologies Inc, Sunnyvale, CA, USA) was refractory period of the atrium and ventricle were measured positioned at the endocardium of the interventricular sep- as described above. tum in the right ventricle through the left femoral vein to After the basal assessment, bepridil was intravenously obtain the monophasic action potential signals, in addition administered at a low dose of 0.3mg/kg over 10min, and to electrically pacing the right ventricle. The signals were each parameter was assessed at 10, 20 and 30min after the amplified with a DC preamplifier (300, EP Technologies start of the drug infusion. Then, additional bepridil was Inc). administered at a high dose of 3mg/kg over 10min, and the The right atrium or right ventricle was electrically driven cardiovascular variables were assessed at 10, 20, 30, 45 and using a cardiac stimulator (SEC-3102; Nihon-Kohden) 60min after the start of the drug infusion. The effects of through the pacing electrodes catheter. The stimulation dl-sotalol at doses of 0.3 and 3mg/kg were assessed in a pulses were rectangular in shape, 1–2V (ie, about twice the manner similar to that of another series of experiments. threshold voltage) and 1ms in duration. The sinus node recovery time was obtained as a pause (in ms) from the last Assessment of theβ-Blocking Action paced atrial depolarization to
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