title: Ranolazine for congenital and acquired late INa-linked arrhythmias: in silico pharmacological screening.
abstract: BACKGROUND
  The antianginal ranolazine blocks the human ether-a-go-go-related gene-based current IKr at therapeutic concentrations and causes QT interval prolongation. Thus, ranolazine is contraindicated for patients with preexisting long-QT and those with repolarization abnormalities. However, with its preferential targeting of late INa (INaL), patients with disease resulting from increased INaL from inherited defects (eg, long-QT syndrome type 3 or disease-induced electric remodeling (eg, ischemic heart failure) might be exactly the ones to benefit most from the presumed antiarrhythmic properties of ranolazine.
  
  
  OBJECTIVE
  We developed a computational model to predict if therapeutic effects of pharmacological targeting of INaL by ranolazine prevailed over the off-target block of IKr in the setting of inherited long-QT syndrome type 3 and heart failure.
  
  
  RESULTS
  We developed computational models describing the kinetics and the interaction of ranolazine with cardiac Na(+) channels in the setting of normal physiology, long-QT syndrome type 3-linked ΔKPQ mutation, and heart failure. We then simulated clinically relevant concentrations of ranolazine and predicted the combined effects of Na(+) channel and IKr blockade by both the parent compound ranolazine and its active metabolites, which have shown potent blocking effects in the therapeutically relevant range. Our simulations suggest that ranolazine is effective at normalizing arrhythmia triggers in bradycardia-dependent arrhythmias in long-QT syndrome type 3 as well tachyarrhythmogenic triggers arising from heart failure-induced remodeling.
  
  
  CONCLUSIONS
  Our model predictions suggest that acute targeting of INaL with ranolazine may be an effective therapeutic strategy in diverse arrhythmia-provoking situations that arise from a common pathway of increased pathological INaL.
authors.affiliation: Tri-Institutional MD-PhD Program, Weill Cornell Medical College/The Rockefeller University/Sloan-Kettering Cancer Institute, New York, New York, USA, 10021.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Moreno
authors.affiliation: Department of Pharmacology, University of California, Davis, Genome Building Rm 3503, Davis, CA 95616-8636.
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Yang
authors.affiliation: Department of Pharmacology Columbia University College of Physicians and Surgeons 630 W. 168th St. New York, NY 10032, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Bankston
authors.affiliation: Department of Pharmacology, University of California, Davis, Genome Building Rm 3503, Davis, CA 95616-8636.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Grandi
authors.affiliation: Department of Pharmacology, University of California, Davis, Genome Building Rm 3503, Davis, CA 95616-8636.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.affiliation: Department of Pharmacology Columbia University College of Physicians and Surgeons 630 W. 168th St. New York, NY 10032, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kass
authors.affiliation: Department of Pharmacology, University of California, Davis, Genome Building Rm 3503, Davis, CA 95616-8636.
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Clancy
mesh_terms: D000083:Acetanilides / Q000494:pharmacology* / Q000627:therapeutic use; D000200:Action Potentials / Q000187:drug effects; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003198:Computer Simulation; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008133:Long QT Syndrome / Q000151:congenital / Q000188:drug therapy*; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D000069458:Ranolazine; D026941:Sodium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D010879:Piperazines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D000069458:Ranolazine
keywords: computational model; heart failure; late INa; long-QT syndrome type 3; ranolazine
references.citation: J Mol Cell Cardiol. 1996 May;28(5):893-903
references.pmid: 8762029
references.citation: J Cardiovasc Electrophysiol. 2008 Dec;19(12):1294-5
references.pmid: 18662183
references.citation: J Mol Cell Cardiol. 2012 Mar;52(3):608-19
references.pmid: 22198344
references.citation: Nature. 1999 Aug 5;400(6744):566-9
references.pmid: 10448858
references.citation: Am J Physiol. 1998 May;274(5):H1643-54
references.pmid: 9612375
references.citation: Circulation. 1995 Dec 15;92(12):3381-6
references.pmid: 8521555
references.citation: Nat Struct Mol Biol. 2004 Mar;11(3):219-25
references.pmid: 14981509
references.citation: Heart. 2006 Jul;92 Suppl 4:iv6-iv14
references.pmid: 16775092
references.citation: Circulation. 1991 Sep;84(3):1364-77
references.pmid: 1653123
references.citation: Am J Physiol Heart Circ Physiol. 2006 Jul;291(1):H29-37
references.pmid: 16501012
references.citation: J Gen Physiol. 2002 Jul;120(1):39-51
references.pmid: 12084774
references.citation: J Cardiovasc Electrophysiol. 2008 Dec;19(12):1289-93
references.pmid: 18662191
references.citation: Circulation. 2006 May 23;113(20):2462-72
references.pmid: 16717165
references.citation: J Physiol. 1997 May 1;500 ( Pt 3):631-42
references.pmid: 9161981
references.citation: J Clin Invest. 1997 Apr 1;99(7):1714-20
references.pmid: 9120016
references.citation: Circulation. 2013 Feb 5;127(5):575-84
references.pmid: 23271797
references.citation: J Clin Invest. 1996 Dec 15;98(12):2874-86
references.pmid: 8981936
references.citation: J Cardiovasc Pharmacol. 2004 Aug;44(2):192-9
references.pmid: 15243300
references.citation: J Mol Cell Cardiol. 2001 May;33(5):923-32
references.pmid: 11343415
references.citation: J Pharmacol Exp Ther. 2004 Aug;310(2):599-605
references.pmid: 15031300
references.citation: Nat Med. 2009 Apr;15(4):380-3
references.pmid: 19330009
references.citation: Br J Pharmacol. 2006 May;148(1):16-24
references.pmid: 16520744
references.citation: Circ Res. 1999 Oct 15;85(8):723-30
references.pmid: 10521246
references.citation: J Clin Invest. 2006 Dec;116(12):3127-38
references.pmid: 17124532
references.citation: Circulation. 2002 May 28;105(21):2543-8
references.pmid: 12034663
references.citation: Am J Cardiol. 1987 Apr 30;59(11):49E-51E
references.pmid: 3578041
references.citation: J Cardiovasc Electrophysiol. 2005 Sep;16(9):981-7
references.pmid: 16174020
references.citation: Prog Cardiovasc Dis. 1988 Sep-Oct;31(2):115-72
references.pmid: 3047813
references.citation: Lancet. 1996 Jul 6;348(9019):7-12
references.pmid: 8691967
references.citation: Sci Transl Med. 2011 Aug 31;3(98):98ra83
references.pmid: 21885405
references.citation: Circ Res. 2001 Apr 13;88(7):740-5
references.pmid: 11304498
references.citation: J Clin Pharmacol. 2005 Apr;45(4):422-33
references.pmid: 15778423
references.citation: Am J Cardiol. 1987 Apr 30;59(11):38E-44E
references.pmid: 2437788
references.citation: J Clin Invest. 2002 Nov;110(9):1251-62
references.pmid: 12417563
references.citation: J Am Coll Cardiol. 1983 Nov;2(5):806-17
references.pmid: 6630761
references.citation: J Pharmacol Exp Ther. 2006 Feb;316(2):718-26
references.pmid: 16234410
references.citation: J Gen Physiol. 1977 Apr;69(4):497-515
references.pmid: 300786
references.citation: Circ Res. 2010 Mar 19;106(5):981-91
references.pmid: 20093630
references.citation: Circulation. 2004 Aug 24;110(8):904-10
references.pmid: 15302796
references.citation: J Physiol. 1990 Aug;427:325-45
references.pmid: 2120426
references.citation: J Cardiovasc Electrophysiol. 2006 May;17 Suppl 1:S169-S177
references.pmid: 16686675
references.citation: J Mol Cell Cardiol. 2010 Jan;48(1):112-21
references.pmid: 19835882
references.citation: Am J Physiol Heart Circ Physiol. 2004 Apr;286(4):H1573-89
references.pmid: 14656705
references.citation: Br J Pharmacol. 2010 May;160(1):60-76
references.pmid: 20331615
references.citation: Biophys J. 2010 Oct 6;99(7):2038-47
references.pmid: 20923637
references.citation: N Engl J Med. 1991 Mar 21;324(12):781-8
references.pmid: 1900101
references.citation: Circulation. 1982 May;65(5):886-94
references.pmid: 6176355
references.citation: J Mol Cell Cardiol. 2001 Apr;33(4):599-613
references.pmid: 11273715
references.citation: Circ Res. 2011 Mar 4;108(5):555-65
references.pmid: 21252154
references.citation: J Gen Physiol. 2003 Mar;121(3):199-214
references.pmid: 12601084
references.citation: Eur J Heart Fail. 2007 Mar;9(3):219-27
references.pmid: 17067855
references.citation: Am J Physiol. 1989 Mar;256(3 Pt 1):C549-59
references.pmid: 2538064
references.citation: J Pharmacol Exp Ther. 1994 Apr;269(1):66-74
references.pmid: 8169853
references.citation: J Am Coll Cardiol. 2007 Mar 13;49(10):1027-34
references.pmid: 17349881
references.citation: Circ Res. 2006 Nov 24;99(11):1225-32
references.pmid: 17082480
references.citation: J Pharmacol Exp Ther. 2009 Nov;331(2):382-91
references.pmid: 19675298
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6309-14
references.pmid: 16606830
references.citation: Circ Res. 1999 Apr 2;84(6):713-21
references.pmid: 10189359
references.citation: Biochemistry. 2000 Feb 15;39(6):1316-23
references.pmid: 10684611
references.citation: Am J Physiol. 1998 Feb;274(2):H477-87
references.pmid: 9486250
references.citation: PLoS Comput Biol. 2011 May;7(5):e1002061
references.pmid: 21637795
references.citation: Heart. 2000 Jun;83(6):661-6
references.pmid: 10814624
references.citation: Eur Heart J. 1988 Dec;9(12):1276-83
references.pmid: 3229422
references.citation: Cardiovasc Res. 1999 May;42(2):530-42
references.pmid: 10533588
references.citation: Cardiovasc Res. 2006 Jan;69(1):116-27
references.pmid: 16223473
references.citation: Am J Physiol. 1999 Nov;277(5):H1817-22
references.pmid: 10564135
references.citation: Nat Med. 2001 Sep;7(9):1021-7
references.pmid: 11533705
references.citation: J Clin Pharmacol. 2005 Jul;45(7):802-9
references.pmid: 15951470
references.citation: J Am Coll Cardiol. 1998 Oct;32(4):1063-7
references.pmid: 9768733
references.citation: Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1088-100
references.pmid: 16565318
references.citation: J Mol Cell Cardiol. 1998 Apr;30(4):829-35
references.pmid: 9602432
references.citation: J Cardiovasc Pharmacol. 2008 Jun;51(6):581-9
references.pmid: 18520952
references.citation: N Engl J Med. 1992 Jul 23;327(4):227-33
references.pmid: 1377359