Akira Takahara

Publications of Akira Takahara

• Discovery and evaluation of selective N-type calcium channel blockers: 6-Unsubstituted-1,4-dihydropyridine-5-carboxylic acid derivatives.

  Authors: Takashi Yamamoto, Seiji Niwa, Munetaka Tokumasu, Tomoyuki Onishi, Seiji Ohno, Masako Hagihara, Hajime Koganei, Shin-Ichi Fujita, Tomoko Takeda, Yuki Saitou, Satoshi Iwayama, Akira Takahara, Seinosuke Iwata, Masataka Shoji

  Bioorganic & medicinal chemistry letters. 04/2012;

  A structure-activity relationship study of 6-unsubstituted-1,4-dihydropyridine and 2,6-unsubstituted-1,4-dihydropyridine derivatives was conducted in an attempt to discover N-type calcium channelA structure-activity relationship study of 6-unsubstituted-1,4-dihydropyridine and 2,6-unsubstituted-1,4-dihydropyridine derivatives was conducted in an attempt to discover N-type calcium channel blockers that were highly selective over L-type calcium channel blockers. Among the tested compounds, (+)-4-(3,5-dichloro-4-methoxy-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-cinnamyl ester was found to be an effective and selective N-type calcium channel blocker with oral analgesic potential.

• Electrophysiological Effects of the Class Ic Antiarrhythmic Drug Pilsicainide on the Guinea-Pig Pulmonary Vein Myocardium.

  Authors: Akira Takahara, Kiyoshi Takeda, Yayoi Tsuneoka, Mihoko Hagiwara, Iyuki Namekata, Hikaru Tanaka

  Journal of pharmacological sciences. 03/2012;

  The pulmonary vein is known as an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation. We compared effects of the class Ic antiarrhythmic drug pilsicainide on theThe pulmonary vein is known as an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation. We compared effects of the class Ic antiarrhythmic drug pilsicainide on the electrophysiological parameters in the isolated pulmonary vein preparation from guinea pigs with those in the left atrium. Three pairs of bipolar electrodes were attached to the left atrium, pulmonary vein, and junctional region of the left atrium and pulmonary vein to measure intra-atrial and intra-pulmonary vein conduction velocity and effective refractory period. Pilsicainide (10 µM) decreased the conduction velocity in the pulmonary vein as well as the left atrium, whose effect on the pulmonary vein was relatively greater than that on the left atrium. The drug prolonged the effective refractory period in the pulmonary vein as well as the left atrium, and the effect of the drug on the pulmonary vein was less than that on the left atrium. The currently observed electrophysiological property of pilsicainide suggests that its effects on reentry within the pulmonary vein are estimated to be weaker than within the left atrium, which may be one of the key considerations for understanding its antiarrhythmic mechanisms in the atrium and pulmonary vein.

• Asymmetric synthesis and biological evaluations of (+)- and (-)-6-dimethoxymethyl-1,4-dihydropyridine-3-carboxylic acid derivatives blocking N-type calcium channels.

  Authors: Takashi Yamamoto, Seiji Ohno, Seiji Niwa, Munetaka Tokumasu, Masako Hagihara, Hajime Koganei, Shin-ichi Fujita, Tomoko Takeda, Yuki Saitou, Satoshi Iwayama, Akira Takahara, Seinosuke Iwata, Masataka Shoji

  Bioorganic & medicinal chemistry letters. 06/2011; 21(11):3317-9.

  An efficient asymmetric synthesis of 1,4-dihydropyridine derivatives is described. The key step is the stereoselective Michael addition using t-butyl ester of L-valine as a chiral auxiliary toAn efficient asymmetric synthesis of 1,4-dihydropyridine derivatives is described. The key step is the stereoselective Michael addition using t-butyl ester of L-valine as a chiral auxiliary to achieve good ee (>95% for all the tested experiments) and moderate yield. With this method, (+)-4-(3-chlorophenyl)-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid cinnamyl ester was obtained and was characterized as a promising N-type calcium channel blocker with improved selectivity over L-type compared to its (-)- and racemic isomers.

• Measurements of cardiac ion channel subunits in the chronic atrioventricular block dog.

  Authors: Akira Takahara, Hirotaka Wagatsuma, Shizuka Aritomi, Tomoyuki Konda, Yasuki Akie, Yuji Nakamura, Atsushi Sugiyama

  Journal of pharmacological sciences. 05/2011; 116(1):132-5.

  The chronic atrioventricular block (CAVB) dog has been widely used as an in vivo proarrhythmia model. mRNA levels of K(+) and Ca(2+) channels in the isolated ventricular tissues from normal and CAVBThe chronic atrioventricular block (CAVB) dog has been widely used as an in vivo proarrhythmia model. mRNA levels of K(+) and Ca(2+) channels in the isolated ventricular tissues from normal and CAVB dogs were assayed using a real-time PCR. The mRNA levels of KvLQT1 and MiRP1 were significantly less in the CAVB heart compared with those in the intact heart, whereas no significant difference was detected in the mRNA levels of other K(+)- or Ca(2+)-channel subunits. Adaptation against chronic bradycardia-related pathophysiology may have decreased the mRNA levels of cardiac K(+) channels, which may partly explain the arrhythmogenic property of this model.

• Electrophysiological and pharmacological characteristics of triggered activity elicited in guinea-pig pulmonary vein myocardium.

  Authors: Akira Takahara, Takahiko Sugimoto, Takuma Kitamura, Kiyoshi Takeda, Yayoi Tsuneoka, Iyuki Namekata, Hikaru Tanaka

  Journal of pharmacological sciences. 02/2011; 115(2):176-81.

  The pulmonary vein is known as an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation. We analyzed electrophysiological and pharmacological characteristics ofThe pulmonary vein is known as an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation. We analyzed electrophysiological and pharmacological characteristics of triggered activity elicited in the isolated pulmonary vein from the guinea pig. Immediately after the termination of train stimulation (pacing cycle length of 100 ms), spontaneous activities accompanied with phase-4 depolarization were detected in 43 out of 45 pulmonary vein preparations. Such triggered activities were not observed in the isolated left atrium. The incidence of triggered activity was higher at a shorter pacing cycle length (100 - 200 ms), and the coupling interval was shorter at a shorter pacing cycle length. Verapamil (1 µM), ryanodine (0.1 µM), and pilsicainide (10 µM) suppressed the occurrence of triggered activities. The resting membrane potential of the pulmonary vein myocardium was more positive than that of the left atrium. Carbachol (0.3 µM) hyperpolarized the resting membrane potential and completely inhibited the occurrence of triggered activities. These results suggest that the pulmonary veins have more arrhythmogenic features than the left atrium, possibly through lower resting membrane potential. The electrophysiological and pharmacological characteristics of triggered activity elicited in the pulmonary vein myocardium were similar to those previously reported using ventricular tissues.

• Developmental changes in action potential prolongation by K+-channel blockers in chick myocardium.

  Authors: Hideaki Nouchi, Naoaki Kiryu, Mikio Kimata, Yayoi Tsuneoka, Shogo Hamaguchi, Iyuki Namekata, Akira Takahara, Koki Shigenobu, Hikaru Tanaka

  Journal of pharmacological sciences. 02/2011; 115(2):235-8.

  The effects of K(+)-channel blockers on the action potential duration of the myocardium were examined in isolated right ventricles from the 7 - 10-day-old, 11 - 13-day-old, and 14 - 20-day-old embryoThe effects of K(+)-channel blockers on the action potential duration of the myocardium were examined in isolated right ventricles from the 7 - 10-day-old, 11 - 13-day-old, and 14 - 20-day-old embryo and 1 - 7-day-old hatched chicks. E-4031 significantly prolonged action potential duration at all developmental stages examined; the prolongation was largest in the 11 - 13-day-old embryo and was accompanied by early after-depolarizations. Chromanol 293B showed smaller prolongation at all stages examined. Terfenadine prolonged action potential duration in the 11 - 13-day-old embryo, but not in other stages. Thus, the chick ventricular myocardium changes its repolarization properties during development.

• Utility of short-term variability of repolarization as a marker for monitoring a safe exercise training program in patients with cardiac diseases.

  Authors: Isao Nishi, Atsushi Sugiyama, Akira Takahara, Kenji Kuroki, Masayuki Igawa, Tsuyoshi Enomoto, Kaname Iida, Susumu Koseki, Kazutaka Aonuma

  International heart journal. 01/2011; 52(5):304-7.

  In order to begin searching for new markers for safe exercise training in patients with cardiac diseases, we tested the sensitivity and reliability of the short-term variability of repolarizationIn order to begin searching for new markers for safe exercise training in patients with cardiac diseases, we tested the sensitivity and reliability of the short-term variability of repolarization (STV(QT)) in comparison with QT interval, QTc, and T(peak)-T(end) interval (T(p-e)) in patients with cardiac diseases. Nine patients (8 men, 1 woman; 58 ± 10 years) were enrolled. The cardiac rehabilitation (CR) program consisted of walking, bicycling on an ergometer, and calisthenics for 30-50 minutes/session and 3-5 sessions/week for 3 months. ECGs of 31 consecutive sinus beats were obtained before and after the CR program. RR and QT intervals were measured in the aVL lead. The mean orthogonal distance from the diagonal to the points of the Poincaré plots was determined using the following equation; STV(QT) [= Σ |QT(n+1)-QT(n)/(30 × 2(1/2))], as a marker of temporal dispersion of repolarization. Also, T(p-e) of 5 consecutive beats was measured as a marker of spatial dispersion. No fatal arrhythmias were observed in the CR. No significant difference was observed in the RR or QT interval between at baseline and at the end of the CR program. Meanwhile, QTc, STV(QT) and T(p-e) decreased significantly from 429 ± 27 to 400 ± 17 (P < 0.01), from 6.8 ± 1.3 to 4.7 ± 1.4 msec (P < 0.001), and from 74.8 (61.2/79.1) to 64.8 (51.4/70.7) msec (median (25th/75th percentile), P < 0.01), respectively. STV(QT) together with T(p-e) and QTc may reflect the time-courses of safe exercise training.

• Blocking effect of NIP-142 on the KCNQ1/KCNE1 channel current expressed in HEK293 cells.

  Authors: Iyuki Namekata, Noriko Tsuruoka, Yayoi Tsuneoka, Tomoyuki Matsuda, Akira Takahara, Yoshio Tanaka, Takeshi Suzuki, Tetsuo Takahashi, Naoko Iida-Tanaka, Hikaru Tanaka

  Biological & pharmaceutical bulletin. 01/2011; 34(1):153-5.

  We examined the effect of NIP-142, a benzopyran compound with terminating effect on experimental atrial arrhythmia, on the KCNQ1/KCNE1 channel, which underlies the slow component of the cardiacWe examined the effect of NIP-142, a benzopyran compound with terminating effect on experimental atrial arrhythmia, on the KCNQ1/KCNE1 channel, which underlies the slow component of the cardiac delayed rectifier potassium channel (I(Ks)). NIP-142, as well as chromanol 293B, showed concentration-dependent blockade of the current expressed in HEK293 cells; the EC(50) value of NIP-142 and chromanol 293B for the inhibition of tail current was 13.2 µM and 4.9 µM, respectively. These results indicate that NIP-142 has blocking effect on the KCNQ1/KCNE1 channel current.

• Effects of S(+)-efonidipine on the rabbit sinus node action potential and calcium channel subunits Ca(V)1.2, Ca(V)1.3 and Ca(V)3.1.

  Authors: Hikaru Tanaka, Iyuki Namekata, Toru Ogawa, Yayoi Tsuneoka, Chisa Komikado, Akira Takahara, Naoko Iida-Tanaka, Hiroko Izumi-Nakaseko, Hiromichi Tsuru, Satomi Adachi-Akahane

  European journal of pharmacology. 12/2010; 649(1-3):263-7.

  The effect of S(+)-efonidipine on sinus node action potential and calcium channel α-subunits was examined. The slope of the phase 4 depolarization of isolated rabbit sinus node tissue wasThe effect of S(+)-efonidipine on sinus node action potential and calcium channel α-subunits was examined. The slope of the phase 4 depolarization of isolated rabbit sinus node tissue was significantly reduced by S(+)-efonidipine (1 μM), slightly reduced by nifedipine (1 μM), but was not affected by R(-)-efonidipine. S(+)-efonidipine (1 μM), inhibited the expressed Ca(V)1.2, Ca(V)1.3 and Ca(V)3.1 channel currents by 75.7%, 75.3% and 94.0%, nifedipine 84.0%, 43.2% and 14.9%, and R(-)-efonidipine 30.0%, 19.6% and 92.8%, respectively. Thus, the prolongation of the phase 4 depolarization of the rabbit sinus node by S(+)-efonidipine may be explained by blockade of the Ca(V)1.3 channel current.

• [Calcium antagonists: current and future applications based on new evidence. Classification of calcium channel blockers].

  Authors: Akira Takahara

  Clinical calcium. 01/2010; 20(1):24-30.

  Calcium channel blockers have been widely recognized as important medicines for the treatment of cardiovascular diseases, including hypertension and angina pectoris. In Japan, more than 15 calciumCalcium channel blockers have been widely recognized as important medicines for the treatment of cardiovascular diseases, including hypertension and angina pectoris. In Japan, more than 15 calcium channel blockers are clinically available, and their pharmacological profiles are known to vary in terms of action on subtypes of voltage-dependent Ca(2+) channels, tissue selectivity, and influence on the sympathetic nerve activity. Thus, the classification of calcium channel blockers is useful for understanding the similarity and differences of the drugs' action, leading to optimum prescription.

• H₂receptor-mediated positive inotropic effect of histamine in neonatal guinea-pig left atria.

  Authors: Naoki Agata, Yoshimitsu Kato, Iyuki Namekata, Akira Takahara, Hikaru Tanaka, Daisuke Chino, Katsuo Koike, Yoshio Tanaka

  Biological & pharmaceutical bulletin. 01/2010; 33(12):2033-5.

  The receptor type mediating the positive inotropic effect of histamine was examined in left atria from neonatal guinea pigs. The positive inotropic effect of histamine, as well as its actionThe receptor type mediating the positive inotropic effect of histamine was examined in left atria from neonatal guinea pigs. The positive inotropic effect of histamine, as well as its action potential prolonging effect, was antagonized by ranitidine, but not by chlorpheniramine or thiperamide. The positive inotropic effect was enhanced by isobutylmethylxantine. Receptor binding studies revealed the presence of both H₁ and H₂ receptor types. These results suggest that the positive inotropic effect of histamine in the neonatal guinea-pig atrium is mediated by H₂ receptors.

• Effect of NIP-142 on potassium channel alpha-subunits Kv1.5, Kv4.2 and Kv4.3, and mouse atrial repolarization.

  Authors: Hikaru Tanaka, Iyuki Namekata, Shogo Hamaguchi, Taro Kawamura, Hiroyuki Masuda, Yoshio Tanaka, Naoko Iida-Tanaka, Akira Takahara

  Biological & pharmaceutical bulletin. 01/2010; 33(1):138-41.

  Effects of NIP-142, a benzopyran compound which terminates experimental atrial arrhythmia, on potassium channel alpha-subunits and mouse atrial repolarization were examined. NIP-142Effects of NIP-142, a benzopyran compound which terminates experimental atrial arrhythmia, on potassium channel alpha-subunits and mouse atrial repolarization were examined. NIP-142 concentration-dependently blocked the outward current through potassium channel alpha subunits Kv1.5, Kv4.2 and Kv4.3 expressed in Xenopus oocytes. In isolated mouse atrial myocardia, NIP-142 prolonged the action potential duration and effective refractory period, and increased the contractile force. These results suggest that NIP-142 blocks the potassium channels underlying the transient and sustained outward currents, which may contribute to its antiarrhythmic activity.

• Cardiovascular Effects of Azelnidipine in Comparison with Those of Amlodipine Assessed in the Halothane-Anaesthetized Dog.

  Authors: Tomomichi Ishizaka, Akira Takahara, Hiroshi Iwasaki, Yoshitaka Mitsumori, Hiroaki Kise, Yuji Nakamura, Atsushi Sugiyama

  Basic & clinical pharmacology & toxicology. 11/2009;

  Azelnidipine is a new dihydropyridine Ca(2+) channel blocker with long plasma half-life. To understand the in vivo cardiovascular profile of azelnidipine, it was assessed in theAzelnidipine is a new dihydropyridine Ca(2+) channel blocker with long plasma half-life. To understand the in vivo cardiovascular profile of azelnidipine, it was assessed in the halothane-anaesthetized, closed-chest canine model and compared with the effect of amlodipine. We administered azelnidipine in doses of 10, 20 and 70 mug/kg, i.v. or amlodipine in doses of 30, 70 and 200 mug/kg, i.v. cumulatively to the animals. The hypotensive effects of azelnidipine and amlodipine were slow in onset and long-lasted, while their extents of dose-related hypotensive effects were similar. Azelnidipine hardly affected the heart rate or plasma noradrenaline concentration at any doses, whereas the high dose of amlodipine increased these parameters. Azelnidipine as well as amlodipine tended to increase the ventricular contraction, which did not achieve statistical significance. During autonomic receptor blockade with atropine and propranolol, neither drug affected the heart rate, ventricular contraction or plasma noradrenaline concentration, although a more significant hypotensive action was observed. These results indicate that azelnidipine and amlodipine do not directly affect cardiac function. Amlodipine may induce sinus tachycardia via reflex-mediated increase in sympathetic tone. Such lack of reflex tachycardia with azelnidipine will provide potential therapeutic strategy for treatment of patients with cardiovascular diseases, being more beneficial than amlodipine.

• Famotidine neither affects action potential parameters nor inhibits human ether-a-go-go-related gene (hERG) K(+) current.

  Authors: Yuji Nakamura, Akira Takahara, Atsushi Sugiyama

  The Journal of toxicological sciences. 10/2009; 34(5):563-7.

  The direct effects of famotidine, a selective histamine H(2) receptor antagonist, on the cardiac repolarization process were assessed using two in vitro test systems. Neither famotidine (0.1 and 1The direct effects of famotidine, a selective histamine H(2) receptor antagonist, on the cardiac repolarization process were assessed using two in vitro test systems. Neither famotidine (0.1 and 1 microM), nor its solvent, dimethylsulfoxide (0.1%), affected any of the action potential parameters of guinea-pig papillary muscles, whereas the positive control, dl-sotalol (30 microM), significantly prolonged the action potential duration. Moreover, neither famotidine (0.1, 1 and 10 microM) nor dimethylsulfoxide affected the human ether-a-go-go-related gene (hERG) K(+) current expressed in Chinese hamster ovary-K1 cells, whereas the positive control, E-4031 (0.1 microM), significantly decreased the current. These results indicate famotidine does not directly affect the cardiac repolarization process.

• Clobutinol delays ventricular repolarization in the guinea-pig heart: comparison with cardiac effects of hERG K+ channel inhibitor E-4031.

  Authors: Akira Takahara, Rieko Sasaki, Mariko Nakamura, Akiko Sendo, Yukiko Sakurai, Iyuki Namekata, Hikaru Tanaka

  Journal of cardiovascular pharmacology. 09/2009;

  Clobutinol has been clinically reported to induce long QT syndrome. To clarify its cardiac electrophysiological properties, we compared effects of clobutinol on the isolated myocardium andClobutinol has been clinically reported to induce long QT syndrome. To clarify its cardiac electrophysiological properties, we compared effects of clobutinol on the isolated myocardium and anesthetized guinea-pig heart with those of a hERG K channel blocker E-4031. In isolated guinea-pig ventricular tissues, clobutinol (3 muM) as well as E-4031 (10-100 nM) prolonged the action potential duration without affecting maximum upstroke velocity, but no further prolongation was observed after application of 30 muM clobutinol. In anesthetized closed-chest guinea pigs, clobutinol (1 and 10 mg/kg, i.v.) and E-4031 (0.01 and 1 mg/kg, i.v.) prolonged the QT interval and duration of the monophasic action potential (MAP) in a dose-dependent manner, and at the same time increased the beat-to-beat variability of the MAP duration, reverse use-dependent prolongation of the MAP duration and triangulation of the MAP configuration. These results suggest that clobutinol delayed the ventricular repolarization and increased the proarrhythmic parameters linked to the hERG K channel inhibitor-induced torsade de pointes arrhythmias.

• Simultaneous Assessment of Pharmacokinetics of Pilsicainide Transdermal Patch and Its Electropharmacological Effects on Atria of Chronic Atrioventricular Block Dogs.

  Authors: Hiroshi Iwasaki, Akira Takahara, Yuji Nakamura, Yoshioki Satoh, Takeshi Nagai, Norihiro Shinkai, Atsushi Sugiyama

  Journal of pharmacological sciences. 08/2009;

  Pharmacokinetics of pilsicainide transdermal patch and its electropharmacological effects were simultaneously assessed using chronic atrioventricular block dogs. After application of the patch (9.8Pharmacokinetics of pilsicainide transdermal patch and its electropharmacological effects were simultaneously assessed using chronic atrioventricular block dogs. After application of the patch (9.8 mg/kg), pilsicainide was continuously absorbed through the skin with a C(max) of 0.49 +/- 0.13 mug/ml, while its plasma concentration was kept above the clinically reported minimum effective plasma concentration for 2 - 8 h. Inter-atrial conduction time was significantly prolonged, whereas statistically significant prolongation was not detected in the atrial effective refractory period. Prolongation of the cycle length of atrial fibrillation and anti-fibrillatory action were confirmed. Thus, pilsicainide can be absorbed transdermally to exert long-lasting electropharmacological effects leading to anti-atrial fibrillatory action.

• Involvement of the Na(+)/Ca(2+) Exchanger in the Automaticity of Guinea-Pig Pulmonary Vein Myocardium as Revealed by SEA0400.

  Authors: Iyuki Namekata, Yayoi Tsuneoka, Akira Takahara, Hideaki Shimada, Takahiko Sugimoto, Kiyoshi Takeda, Midori Nagaharu, Koki Shigenobu, Toru Kawanishi, Hikaru Tanaka

  Journal of pharmacological sciences. 06/2009; 110(1):111-6.

  We examined the involvement of the Na(+)/Ca(2+) exchanger in the automaticity of the pulmonary vein myocardium with a specific inhibitor, SEA0400. Action potentials were recorded from the myocardialWe examined the involvement of the Na(+)/Ca(2+) exchanger in the automaticity of the pulmonary vein myocardium with a specific inhibitor, SEA0400. Action potentials were recorded from the myocardial layer of isolated guinea-pig pulmonary vein preparations, and Ca(2+) transients were recorded from the cardiomyocytes. Spontaneous electrical activity was observed in 17.7% of the preparations, which was inhibited by either SEA0400 or ryanodine. In quiescent preparations, ouabain induced electrical activity and spontaneous Ca(2+) transients, which were inhibited by SEA0400, as well as ryanodine. These results provide pharmacological evidence that the Na(+)/Ca(2+) exchanger underlies the automaticity of the pulmonary vein myocardium.

• New aspects for the treatment of cardiac diseases based on the diversity of functional controls on cardiac muscles: diversity in the excitation-contraction mechanisms of the heart.

  Authors: Hikaru Tanaka, Iyuki Namekata, Hideaki Nouchi, Koki Shigenobu, Toru Kawanishi, Akira Takahara

  Journal of pharmacological sciences. 04/2009; 109(3):327-33.

  The waveform of the myocardial action potential (AP) triggering contraction differs among the species, developmental stage, and pathological state. The species difference in heart rate, whichThe waveform of the myocardial action potential (AP) triggering contraction differs among the species, developmental stage, and pathological state. The species difference in heart rate, which inversely correlates with body size, originates in the ion-channel mechanisms responsible for diastolic depolarization of the sinoatrial node. In some cases, such as the chronically AV-blocked dog and 11- to 13-day chick embryo, the repolarization reserve is decreased making the heart useful for drug evaluation. The degree of dependence of contraction on sarcoplasmic reticulum (SR) function increases during development. The large SR dependence and short AP of the adult mouse and rat support their rapid contraction under high heart rate. The function of the Na(+)/Ca(2+) exchanger is affected by AP waveform and ion concentrations; its major role is Ca(2+) extrusion, but under pathological conditions such as ischemia-reperfusion, it allows Ca(2+) influx and leads to myocardial injury, including loss of mitochondrial function. The role of mitochondria in ATP supply is less in the fetus where glycolysis plays a greater role. The pharmacological properties of the myocardium are affected by all of these factors and also by autonomic innervation and the hormonal status. Such comprehensive understanding is indispensable for the development of novel therapeutic strategies.

• Cilnidipine: a new generation ca channel blocker with inhibitory action on sympathetic neurotransmitter release.

  Authors: Akira Takahara

  Cardiovascular therapeutics. 02/2009; 27(2):124-39.

  Cilnidipine is a unique Ca(2+) channel blocker with an inhibitory action on the sympathetic N-type Ca(2+) channels, which is used for patients with hypertension in Japan. Cilnidipine has beenCilnidipine is a unique Ca(2+) channel blocker with an inhibitory action on the sympathetic N-type Ca(2+) channels, which is used for patients with hypertension in Japan. Cilnidipine has been clarified to exert antisympathetic actions in various examinations from cell to human levels, in contrast to classical Ca(2+) channel blockers. Furthermore, renoprotective and neuroprotective effects as well as cardioprotective action of cilnidipine have been demonstrated in clinical practice or animal examinations. After the introduction of nifedipine as an antihypertensive drug, many Ca(2+) channel blockers with long-lasting action for blood pressure have been developed to minimize sympathetic reflex during antihypertensive therapy, which have been divided into three groups; namely, first, second, and third generation based on their pharmacokinetic profiles. Since cilnidipine directly inhibits the sympathetic neurotransmitter release by N-type Ca(2+) channel-blocking property, the drug can be expected as fourth generation, providing an effective strategy for the treatment of cardiovascular diseases.

• Chronic left atrial volume overload abbreviates the action potential duration of the canine pulmonary vein myocardium via activation of IK channel.

  Authors: Hideaki Nouchi, Akira Takahara, Hideki Nakamura, Iyuki Namekata, Takahiko Sugimoto, Yayoi Tsuneoka, Kiyoshi Takeda, Toshikazu Tanaka, Koki Shigenobu, Atsushi Sugiyama, Hikaru Tanaka

  European journal of pharmacology. 10/2008;

  Electrophysiological properties of the pulmonary vein myocardium were assessed in a canine chronic atrioventricular block model resulting in left atrial volume overload. Five chronic atrioventricularElectrophysiological properties of the pulmonary vein myocardium were assessed in a canine chronic atrioventricular block model resulting in left atrial volume overload. Five chronic atrioventricular block dogs and five sham-operated dogs were used. The heart was removed two months after a surgical procedure causing atrioventricular block, when atrial structural remodeling was established. Standard microelectrode penetrations were made with glass microelectrodes to obtain action potential signals of left atrium and pulmonary vein myocardia. The resting membrane potential in the pulmonary vein was more positive than that in the left atrium (-69 mV vs -74 mV) in both animal groups. The action potential duration at 50% repolarization of the pulmonary vein was shorter in the chronic atrioventricular block dogs than in the sham-operated dogs (38 ms vs 63 ms), whereas no significant difference was detected in the action potential duration of the left atrium between the two animal groups (67 ms vs 61 ms). The action potential duration of the pulmonary vein in the chronic atrioventricular block dogs was prolonged by charybdotoxin but not by iberiotoxin. Such prolongation was not observed in the normal pulmonary vein. These results suggest that long-term left atrial dilatation shortened the action potential duration of pulmonary vein myocardium, which may be associated with activation of the intermediate conductance Ca(2+)-activated K(+) channel (IK channel).