The Heart Rate‐Lowering Agent Ivabradine Inhibits the Pacemaker Current If in Human Atrial Myocytes

Introduction: It has been speculated that pacemaker current (If) in human atria could play a role in causing ectopic atrial automaticity. Ivabradine is a novel selective and specific If inhibitor in the sinus node that reduces heart rate without any negative inotropic effect. The aim of the study was to explore possible effects of ivabradine on If in atrial myocytes.

[1]  L. Lai,et al.  Measurement of Funny Current (If) Channel mRNA in Human Atrial Tissue: Correlation with Left Atrial Filling Pressure and Atrial Fibrillation , 1999, Journal of cardiovascular electrophysiology.

[2]  M. Biel,et al.  A family of hyperpolarization-activated mammalian cation channels , 1998, Nature.

[3]  D. DiFrancesco.  Serious workings of the funny current. , 2006, Progress in biophysics and molecular biology.

[4]  B. Santoro,et al.  The HCN Gene Family: Molecular Basis of the Hyperpolarization‐Activated Pacemaker Channels , 1999, Annals of the New York Academy of Sciences.

[5]  L. Puybasset,et al.  Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. , 1995, The Journal of pharmacology and experimental therapeutics.

[6]  Akinori Noma,et al.  Molecular Characterization of the Hyperpolarization-activated Cation Channel in Rabbit Heart Sinoatrial Node* , 1999, The Journal of Biological Chemistry.

[7]  R. Shigemoto,et al.  HCN2 and HCN4 Isoforms Self-assemble and Co-assemble with Equal Preference to Form Functional Pacemaker Channels* , 2007, Journal of Biological Chemistry.

[8]  Martin Biel,et al.  Two pacemaker channels from human heart with profoundly different activation kinetics , 1999, The EMBO journal.

[9]  R. Longhi,et al.  Hyperpolarization-activated Cyclic Nucleotide-gated Channel 1 Is a Molecular Determinant of the Cardiac Pacemaker Current I f * , 2001, The Journal of Biological Chemistry.

[10]  A Mugelli,et al.  Effect of 5-HT4 receptor stimulation on the pacemaker current I(f) in human isolated atrial myocytes. , 1998, Cardiovascular research.

[11]  U. Kaupp,et al.  Molecular diversity of pacemaker ion channels. , 2001, Annual review of physiology.

[12]  L. Boscá,et al.  Regional distribution of hyperpolarization‐activated current (If) and hyperpolarization‐activated cyclic nucleotide‐gated channel mRNA expression in ventricular cells from control and hypertrophied rat hearts , 2003, The Journal of physiology.

[13]  Stefan Herzig,et al.  Single-Channel Properties Support a Potential Contribution of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels and If to Cardiac Arrhythmias , 2005, Circulation.

[14]  D DiFrancesco,et al.  Pacemaker mechanisms in cardiac tissue. , 1993, Annual review of physiology.

[15]  Dario DiFrancesco,et al.  Direct activation of cardiac pacemaker channels by intracellular cyclic AMP , 1991, Nature.

[16]  D. Beuckelmann,et al.  Characterization of the hyperpolarization-activated inward current in isolated human atrial myocytes. , 1998, Cardiovascular research.

[17]  Jean-Claude Tardif,et al.  Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. , 2005, European heart journal.

[18]  J. Olgin,et al.  Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation. , 2000, Circulation.

[19]  L. Hittinger,et al.  Heart rate reduction during exercise-induced myocardial ischaemia and stunning. , 2004, European heart journal.

[20]  X. Monnet,et al.  Effects of heart rate reduction with ivabradine on exercise-induced myocardial ischemia and stunning. , 2001, The Journal of pharmacology and experimental therapeutics.

[21]  D. DiFrancesco,et al.  Current-dependent Block of Rabbit Sino-Atrial Node If Channels by Ivabradine , 2002, The Journal of general physiology.

[22]  G. Lerebours,et al.  Pharmacological Basics of ƒ-Current Inhibition , 2005, Heart Drug.

[23]  G Sani,et al.  Characterization of the hyperpolarization-activated current, I(f), in ventricular myocytes from human failing heart. , 1997, Circulation.

[24]  Martin Biel,et al.  Cardiac HCN channels: structure, function, and modulation. , 2002, Trends in cardiovascular medicine.

[25]  D. Mckinnon,et al.  Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. , 1999, Circulation research.

[26]  D. Escande,et al.  A hyperpolarization-activated inward current in human myocardial cells. , 1992, Journal of molecular and cellular cardiology.

[27]  E. Kandel,et al.  Interactive cloning with the SH3 domain of N-src identifies a new brain specific ion channel protein, with homology to eag and cyclic nucleotide-gated channels. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[28]  J. Péglion,et al.  Stereospecific in vitro and in vivo effects of the new sinus node inhibitor (+)-S 16257. , 1997, European journal of pharmacology.

[29]  J. Lenfant,et al.  Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells , 1996, British journal of pharmacology.

[30]  T. Opthof.  The membrane current (I(f)) in human atrial cells: implications for atrial arrhythmias. , 1998, Cardiovascular Research.

[31]  H. Sullivan.  Ionic Channels of Excitable Membranes, 2nd Ed. , 1992, Neurology.

[32]  Klaus Zorn-Pauly,et al.  If in left human atrium: a potential contributor to atrial ectopy. , 2004, Cardiovascular research.

[33]  A. Mugelli,et al.  I(f) in non-pacemaker cells: role and pharmacological implications. , 2006, Pharmacological research.

[34]  M. Biel,et al.  Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. , 2001, European journal of biochemistry.

[35]  J. Borer.  Heart rate slowing by If inhibition: therapeutic utility from clinical trials , 2005 .

[36]  D. DiFrancesco,et al.  Properties of ivabradine‐induced block of HCN1 and HCN4 pacemaker channels , 2006, The Journal of physiology.

[37]  J. Vilaine,et al.  Anti-Ischemic Effects of Ivabradine, a Selective Heart Rate-Reducing Agent, in Exercise-Induced Myocardial Ischemia in Pigs , 2003, Journal of cardiovascular pharmacology.

[38]  J. Rossier,et al.  AMPA receptor subunits expressed by single purkinje cells , 1992, Neuron.

[39]  P. Chomarat,et al.  Use‐dependent inhibition of hHCN4 by ivabradine and relationship with reduction in pacemaker activity , 2007, British journal of pharmacology.

[40]  L. Hittinger,et al.  Contributions of heart rate and contractility to myocardial oxygen balance during exercise. , 2003, American journal of physiology. Heart and circulatory physiology.

[41]  M. Biel,et al.  Structure and Function of Cardiac Pacemaker Channels , 1999, Cellular Physiology and Biochemistry.

[42]  A Mugelli,et al.  The pacemaker current If in single human atrial myocytes and the effect of β‐adrenoceptor and A1‐adenosine receptor stimulation , 1997, British journal of pharmacology.