Cardiovascular Effects of an L/N-Type Ca Channel Blocker Cilnidipine
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J Pharmacol Sci 96, 219 – 223 (2004) Journal of Pharmacological Sciences ©2004 The Japanese Pharmacological Society Short Communication Cardiovascular Effects of an L/N-type Ca2+ Channel Blocker Cilnidipine Assessed in the Chronic Atrioventricular Conduction Block Dogs Akira Takahara1,2, Atsushi Sugiyama2,*, Yoshioki Satoh2, Yuji Nakamura2, and Keitaro Hashimoto2 1Pharmaceutical Research Laboratories, Pharmaceuticals Company, Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki 210-8681, Japan 2Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Tamaho-cho, Nakakoma-gun, Yamanashi 409-3898, Japan Received July 8, 2004; Accepted August 13, 2004 Abstract. Cardiovascular effects of cilnidipine, a dual L/N-type Ca2+ channel blocker, were evaluated in the chronic atrioventricular block dogs, of which systemic blood pressure and plasma catecholamine levels significantly increased in the pre-drug control. Administration of antihypertensive doses of cilnidipine (1 and 3 g/kg, i.v.) significantly decreased the total peri- pheral vascular resistance, mean blood pressure, and atrial rate and increased the cardiac output. These results suggest that cilnidipine not only decreases the blood pressure, but also decreases the sinus automaticity in the in vivo hypertensive condition with increased adrenergic tones. Keywords: cilnidipine, chronic AV block dog, sympathetic nerve activity Cilnidipine is an L/N-type Ca2+ channel blocker used completed within 4 weeks after the onset of AV block for patients with essential hypertension (1). In previous (6 – 8), the cardiovascular effects of cilnidipine were studies, cilnidipine has been shown to suppress cate- assessed 4 weeks after the surgery. Venous blood was cholamine release from the sympathetic nerve endings withdrawn from 3 out of 5 chronic AV block dogs in via its N-type Ca2+ channel-blocking property, leading to the resting condition, and plasma concentrations of in vivo anti-sympathetic effects, which does not activate catecholamines and atrial natriuretic peptide were reflex tachycardia during antihypertensive therapies determined using a high-performance liquid chromato- (1 – 4). Furthermore, we have shown that cilnidipine graphic technique and radioimmunoassay, respectively selectively suppresses the sympathetic nerve-mediated (SRL Co., Tokyo). chronotropic responses, but it does not affect the The dogs were anesthetized with pentobarbital parasympathetic nerve-mediated responses (5). In the sodium (30 mg/kg, i.v.), and artificially ventilated with present study, we assessed cardiovascular effects of room air. A heparinized catheter was placed in the aorta cilnidipine on the chronic atrioventricular (AV) block to measure the systemic blood pressure. A thermodilu- dogs, where severe long-lasting bradycardia and volume tion catheter (TC-704; Nihon-Kohden, Tokyo) was overload produced histological, structural, and electro- positioned at the right side of the heart to monitor the physiological remodelings of the heart together with pulmonary arterial pressure, pulmonary capillary wedge neurohumoral responses (6, 7). pressure, and right atrial pressure. Cardiac output was All experiments were performed according to Guide- measured by a standard thermodilution method with a lines for Animal Experiments, University of Yamanashi cardiac output computer (MFC-1100, Nihon-Kohden). and Ajinomoto Co., Inc. Five beagle dogs weighing Total peripheral vascular resistance (TPR) was calcu- about 10 kg were used in this study. The complete AV lated using the basic equation: TPR mean blood block was induced using the catheter ablation technique, pressure / cardiac output. The surface lead II ECG was as previously described (6). Since the anatomical and obtained from the limb electrodes. A bi-directional electrophysiological remodelings have been shown to be steerable MAP recording/pacing combination catheter (1675P; EP Technologies, Sunnyvale, CA, USA) was *Corresponding author. FAX: +81-55-273-6739 positioned at the endocardium of the interventricular E-mail: [email protected] 219 220 A Takahara et al septum of the right ventricle. The duration of the MAP TRP MAP90 ERP, which indicates the extent of the signal was measured at 90% repolarization level as electrical vulnerability of the ventricular muscle (9). MAP90. The heart was electrically driven using a cardiac The parameters were continuously monitored using stimulator (SEC-3102, Nihon-Kohden) with the pacing a polygraph system (RM-6000, Nihon-Kohden) and electrodes of the MAP recording/pacing combination analyzed with a real time full automatic data analysis catheter in the right ventricle. Stimulation pulses were system (MP/VAS 3 for Macintosh, ver 1.0; Physio- rectangular in shape, 1–2V (about twice the threshold Tech, Tokyo). Cilnidipine (Ajinomoto, Tokyo) was dis- voltage) and 1-ms duration. MAP90 was measured during solved in vehicle containing 15% ethanol, 15% poly- the ventricular rhythm and at each pacing cycle length of ethylene glycol 400, and 70% saline. After the assess- 300 – 1000 ms. Effective refractory period (ERP) was ment of the basal condition, cilnidipine in a dose of assessed by programmed electrical stimulation to the 1 g/kg was intravenously administered over 10 min right ventricle. The pacing protocol consisted of five and each parameter was assessed 10, 20 and 30 min after beats of basal stimuli in each cycle length followed by the start of the drug infusion. Next, cilnidipine in a dose an extra stimulus of various coupling intervals. The of 3 g/kg was additionally administered over 10 min duration of terminal repolarization phase (TRP) of the and each parameter was assessed 10, 20, 30, 45, and ventricle, namely, phase 3 repolarization of the action 60 min after the start of the drug infusion. potential, was calculated by the following equation; Data are expressed as the mean M S.E.M. The statisti- cal comparisons within a parameter were evaluated by one-way, repeated-measures analysis of variance fol- lowed by Contrasts for mean values comparison. A P Table 1. Hemodynamic and hormonal characteristics of the chronic atrioventricular block dogs SBP (mmHg) systolic 222 M 10 mean 139 M 3 diastolic 104 M 6 PBP (mmHg) systolic 40 M 8 mean 16 M 2 diastolic 6 M 1 AR (beats/min) 165 M 14 IVR (beats/min) 47 M 3 RAP (mmHg) 8 M 1 PCWP (mmHg) 10 M 2 CI (l/min per m2)2.92M 0.29 CO (l/min) 1.53 M 0.14 TPR (mmHg min/l) 95 M 11 MAP90 (ms) 285 M 22 NE (pg/ml) 439 M 30 Epi (pg/ml) 646 M 169 DA (pg/ml) 25 M 1 ANP (pg/ml) 73 M 9 Data are each a mean M S.E.M. Cardiohemodynamic variables were obtained from 5 animals, while hormonal data were derived from 3 out of 5 animals. SBP, systemic blood pressure; PBP, pulmonary Fig. 1. Typical tracings of the surface lead II electrocardiogram blood pressure, AR, atrial rate; IVR, idioventricular rate; RAP, right (ECG), monophasic action potentials recorded from the right atrial pressure; PCWP, pulmonary capillary wedge pressure; CI, ventricle (MAP), and systemic or pulmonary blood pressures during cardiac index; CO, cardiac output; TPR, total peripheral vascular the idioventricular rhythm in the anesthetized chronic atrioventriculr resistance; MAP90, duration of monophasic action potential at a level block dog. Upper panel shows these tracings at pre-drug control, of 90% repolarization; NE, plasma norepinephrine concentration; while the lower panel shows these tracings 10 min after the start of Epi, plasma epinephrine concentration; DA, plasma dopamine intravenous administration of cilnidipine in a dose of 3 g/kg. concentration; ANP, plasma atrial natriuretic peptide concentration. Chronic AV Block Dog and Cilnidipine 221 value 0.05 was considered statistically significant. additional treatment with the high dose, the diastolic and Typical tracings of the electrocardiogram, mono- mean blood pressure decreased for 10 – 45 min and for phasic action potential signal, systemic blood pressure 10 – 20 min, respectively, and atrial rate decreased at 10, and pulmonary arterial pressure of the chronic AV block 20, 45 and 60 min. No significant changes were detected dog are depicted in Fig. 1, while pre-drug values of the in the idioventricular rate. hemodynamic and hormonal parameters are summarized The time courses of the changes in the pulmonary in Table 1. arterial pressure, right atrial pressure and pulmonary The time courses of the changes in the systemic blood capillary wedge pressure are shown in Fig. 2 (right pressure, atrial rate and idioventricular rate are shown panel). After the low dose, the systolic and mean in Fig. 2 (left panel). After the low dose of cilnidipine, pulmonary arterial pressure increased at 10 min and the diastolic blood pressure and atrial rate decreased at for 10 – 20 min, respectively. After the high dose, the 10 min and for 10 – 30 min, respectively. After an systolic and mean pulmonary arterial pressure increased Fig. 2. Time courses of the effects of cilnidipine on the systemic blood pressure, atrial rate, idioventricular rate, monophasic action potential duration at a level of 90% repolarization (MAP90) during the idioventricular rhythm, pulmonary arterial pressure, right atrial pressure, pulmonary capillary wedge pressure (PCWP), cardiac output, and vascular resistance. Data are presented as the mean M S.E.M. (n 5). Closed symbols represent the significant differences from each pre-drug control (C) value at P0.05. 222 A Takahara et al for 10 – 20 min and for 10 – 45 min, respectively. No while