Effects of new class III antiarrhythmic drug niferidil on electrical activity in murine ventricular myocardium and their ionic mechanisms

详细信息    查看全文

• 作者：Denis V. Abramochkin ; Vladislav S. Kuzmin…
• 关键词：Antiarrhythmic drug ; Atrial fibrillation ; Action potential ; Ionic currents ; I Kur ; Atrial ; selective
• 刊名：Naunyn-Schmiedeberg's Archives of Pharmacology
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：388
• 期：10
• 页码：1105-1112
• 全文大小：1,192 KB
• 参考文献：Brouillette J, Clark RB, Giles WR, Fiset C (2004) Functional properties of K+ currents in adult mouse ventricular myocytes. J Physiol 559:777-98PubMed Central CrossRef PubMed
  Camm AJ, Lip GYH, Caterina R, Savelieva I, et al (2012) ESC Committee for Practice Guidelines (CPG). 2012 focused update of the ESC Guidelines for the management of atrial fibrillation. Eur Heart J 33:2719-747CrossRef PubMed
  Fedorov VV, Sharifov OF, Beloshapko GG, Yushmanova AV, Rosenshtraukh LV (2000) Effects of a new class III antiarrhythmic drug nibentan in a canine model of vagally mediated atrial fibrillation. J Cardiovasc Pharmacol 36:77-9CrossRef PubMed
  Fedorov VV, Rosenshtraukh LV, Reznik AV, et al (2004) Antiarrhythmic efficacy of a new class III antiarrhythmic drug RG-2. Kardiologiia 44:66-4PubMed
  Finnin M (2010) Vernakalant: a novel agent for the termination of atrial fibrillation. Am J Health Syst Pharm 67:1157-164CrossRef PubMed
  Glushkov RG, Yuzhakov SD, L’vov AI, et al (2011) New group of class III antiarrhythmic drugs: piperid-4-ylethane derivatives. Pharm Chem J 45:3-2
  Golitsyn SP, Yuricheva YA, Maykov EB, et al (2011) Intravenous niferidil, a new class III antiarrhythmic agent, for termination of persistent atrial fibrillation and flutter. Circulation 124:A10356 Abstract
  Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y (2010) Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev 90:291-66CrossRef PubMed
  Isenberg G, Klockner U (1982) Calcium tolerant ventricular myocytes prepared by preincubation in a ‘KB-medium- Pflugers Arch 395:6-8CrossRef PubMed
  Jahnel U, Klemm P, Nawrath H (1994) Different mechanisms of the inhibition of the transient outward current in rat ventricular myocytes. Naunyn Schmiedeberg's Arch Pharmacol 349:87-4
  Kamkin A, Kiseleva I, Isenberg G (2000) Stretch-activated currents in ventricular myocytes: amplitude and arrhythmogenic effects increase with hypertrophy. Cardiovasc Res 48:409-20CrossRef PubMed
  Li GR, Feng J, Yue L, Carrier M, Nattel S (1996) Evidence for two components of delayed rectifier K+ current in human ventricular myocytes. Circ Res 78:689-96CrossRef PubMed
  Liu GX, Zhou J, Koren G (2008) Single-channel properties of IK,slow1 and IK,slow2 in mouse ventricular myocytes. Pflugers Arch - Eur J Physiol 456:541-47CrossRef
  Mashkovsky MD, Glushkov RG, Dorodnikova SD, et al (1995) The search for antiarrhythmic drug among the derivatives of 1,5-diaminopentane. Khim Farm Zh 3:27-1
  Maykov EB, Yuricheva YA, Mironov NY, et al (2014) Efficacy of a new class III drug niferidil in cardioversion of persistent atrial fibrillation and flutter. J Cardiovasc Pharmacol 64:247-55CrossRef PubMed
  Nattel S, Yue L, Wang Z (1999) Cardiac ultrarapid delayed rectifiers: a novel potassium current family of functional similarity and molecular diversity. Cell Physiol Biochem 9:217-26CrossRef PubMed
  Regan CP, Kiss L, Stump GL, et al (2008) Atrial antifibrillatory effects of structurally distinct IKur blockers 3-[(dimethylamino)methyl]-6-methoxy-2-methyl-4-phenylisoquinolin-1(2?H)-one and 2-phenyl-1,1-dipyridin-3-yl-2-pyrrolidin-1-yl-ethanol in dogs with underlying heart failure. J Pharmacol Exp Ther 324:322-30CrossRef PubMed
  Reisinger J, Gatterer E, Lang W, et al (2004) Flecainide versus ibutilide for immediate cardioversion of atrial fibrillation of recent onset. Eur Heart J 25:1318-324CrossRef PubMed
  Reznik AV, Fedorov VV, Kokoz YM, et al (2003) Ionic mechanisms of cardiotropic action of a new class III antiarrhythmic drug RG-2. Kardiologiia 43:76-2PubMed
  Rosenshtraukh LV, Fedorov VV, Reznik AV, et al (2003) Electrophysiological experimental study of a novel class III antiarrhythmic drug RG-2. Kardiologiia 43:56-3
  Sridhar A, da Cunha DN, Lacombe VA, et al (2007) The plateau outward current in canine ventricle, sensitive to 4-aminopyridine, is a constitutive contributor to ventricular repolarization. Br J Pharmacol 152:870-79PubMed Central CrossRef PubMed
  Xu H, Guo W, Nerbonne JM (1999) Four kinetically distinct depolarization-activated K+ currents in adult mouse ventricular myocytes. J Gen Physiol 113:661-77PubMed Central CrossRef PubMed
  Zhang X, Anderson JW, Fedida D (1997) Characterization of nifedipine block of the human heart delayed rectifier, hKv1.5. J Pharmacol Exp Ther 281:1247-256PubMed
  
• 作者单位：Denis V. Abramochkin (1) (2)
  Vladislav S. Kuzmin (1) (3)
  Leonid V. Rosenshtraukh (3)
  
  1. Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskije gory, 1, 12, 119991, Moscow, Russia
  2. Department of Physiology, Pirogov Russian National Research Medical University, Moscow, Russia
  3. Institute of Experimental Cardiology, Moscow, Russia
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Pharmacology and Toxicology
  Neurosciences
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1912

文摘

A new class III antiarrhythmic drug niferidil has been recently introduced as a highly effective therapy cure for cases of persistent atrial fibrillation, but ionic mechanisms of its action are still unknown. Effects of niferidil on action potential (AP) waveform and major ionic currents were studied in mouse ventricular myocardium. APs were recorded with glass microelectrodes in multicellular preparations of right ventricular wall. Whole-cell patch-clamp technique was used to measure K+, Ca2+, and Na+ currents in isolated mouse ventricular myocytes. While 10? M niferidil failed to alter the AP configuration, 10? M tended to prolong APs (by 12.05 ± 1.8 % at 50 % of repolarization) and 10? M induced significant slowing of repolarization (32.1 ± 4.9 % at 50 % of repolarization). Among the potassium currents responsible for AP repolarization phase, I _K1 was found to be almost insensitive to niferidil. I _to demonstrated low sensitivity to niferidil with IC50 = 2.03 × 10? M. I _Kur, which was previously hypothesized to be the main target of the drug, was more sensitive with IC50 = 6 × 10? M. However, sustained delayed rectifier potassium current I _ss was inhibited with even lower IC50 = 2.8 × 10? M. Therefore, suppression of I _ss and, second, I _Kur by niferidil seems to underlie the AP prolongation in mouse ventricular tissue. Niferidil also produced a modest decrease in I _CaL peak amplitude (IC50?0? M), but failed to alter I _Na significantly. Niferidil prolongs APs in mouse ventricular myocardium mainly by inhibiting I _ss and I _Kur K+ currents, but not exclusively I _Kur, as was proposed earlier. Further investigations are required to reveal the mechanisms of niferidil action in human myocardium, where I _Kr is strongly expressed instead of I _ss. Keywords Antiarrhythmic drug Atrial fibrillation Action potential Ionic currents I _Kur Atrial-selective