title: Field and action potential recordings in heart slices: correlation with established in vitro and in vivo models.
abstract: OBJECTIVE
  Action potential (AP) recordings in ex vivo heart preparations constitute an important component of the preclinical cardiac safety assessment according to the ICH S7B guideline. Most AP measurement models are sensitive, predictive and informative but suffer from a low throughput. Here, effects of selected anti-arrhythmics (flecainide, quinidine, atenolol, sotalol, dofetilide, nifedipine, verapamil) on field/action potentials (FP/AP) of guinea pig and rabbit ventricular slices are presented and compared with data from established in vitro and in vivo models.
  
  
  METHODS
  Data from measurements of membrane currents (hERG, I(Na) ), AP/FP (guinea pig and rabbit ventricular slices), AP (rabbit Purkinje fibre), haemodynamic/ECG parameters (conscious, telemetered dog) were collected, compared and correlated to complementary published data (focused literature search).
  
  
  RESULTS
  The selected anti-arrhythmics, flecainide, quinidine, atenolol, sotalol, dofetilide, nifedipine and verapamil, influenced the shape of AP/FP of guinea pig and rabbit ventricular slices in a manner similar to that observed for rabbit PF. The findings obtained from slice preparations are in line with measurements of membrane currents in vitro, papillary muscle AP in vitro and haemodynamic/ECG parameters from conscious dogs in vivo, and were also corroborated by published data.
  
  
  CONCLUSIONS
  FP and AP recordings from heart slices correlated well with established in vitro and in vivo models in terms of pharmacology and predictability. Heart slice preparations yield similar results as papillary muscle but offer enhanced throughput for mechanistic investigations and may substantially reduce the use of laboratory animals.
authors.affiliation: Safety Pharmacology, Bayer HealthCare AG, Wuppertal, Germany. herbert.himmel@bayer.com
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Himmel
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bussek
authors.forename: Michael
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Rolf
authors.initials: R
authors.lastname: Beckmann
authors.forename: Horst
authors.initials: H
authors.lastname: Lohmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmidt
authors.forename: Erich
authors.initials: E
authors.lastname: Wettwer
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000826:Animal Testing Alternatives; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D011690:Purkinje Fibers / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D013045:Species Specificity
chemical_list: D000889:Anti-Arrhythmia Agents
references.citation: Br J Clin Pharmacol. 1997 Oct;44(4):403-9
references.pmid: 9354317
references.citation: Eur J Clin Pharmacol. 1981;20(2):85-9
references.pmid: 7262178
references.citation: Cardiovasc Res. 2003 Apr 1;58(1):32-45
references.pmid: 12667944
references.citation: J Cardiovasc Pharmacol Ther. 2012 Mar;17(1):86-92
references.pmid: 21527783
references.citation: Pharmacol Ther. 2009 Aug;123(2):255-78
references.pmid: 19460403
references.citation: Fundam Clin Pharmacol. 2006 Feb;20(1):1-8
references.pmid: 16448390
references.citation: J Cardiovasc Pharmacol. 1997 Oct;30(4):489-96
references.pmid: 9335409
references.citation: J Pharmacol Exp Ther. 1986 Apr;237(1):232-6
references.pmid: 3958966
references.citation: J Mol Cell Cardiol. 1991 Feb;23 Suppl 1:103-14
references.pmid: 2038070
references.citation: Pflugers Arch. 1989 Sep;414(5):600-12
references.pmid: 2780225
references.citation: Br Med J. 1979 May 5;1(6172):1184
references.pmid: 445002
references.citation: Eur Heart J. 1987 May;8(5):544-8
references.pmid: 3609048
references.citation: J Pharmacol Exp Ther. 1996 Aug;278(2):597-606
references.pmid: 8768709
references.citation: Eur J Pharmacol. 2000 Aug 4;401(2):137-43
references.pmid: 10924918
references.citation: Eur J Pharmacol. 1992 Apr 22;214(2-3):191-7
references.pmid: 1325356
references.citation: J Cardiovasc Pharmacol. 2000 Jul;36(1):132-9
references.pmid: 10892671
references.citation: Drug Saf. 2006;29(3):237-54
references.pmid: 16524323
references.citation: Circ Res. 2008 May 9;102(9):e86-100
references.pmid: 18436794
references.citation: Cardiovasc Res. 1986 Oct;20(10):705-9
references.pmid: 2878723
references.citation: Am Heart J. 1983 Oct;106(4 Pt 2):829-39
references.pmid: 6412533
references.citation: J Pharmacol Toxicol Methods. 2007 Sep-Oct;56(2):145-58
references.pmid: 17590357
references.citation: J Pharm Pharmacol. 1986 Apr;38(4):316-9
references.pmid: 2872302
references.citation: Biophys J. 1998 Jan;74(1):230-41
references.pmid: 9449325
references.citation: J Pharmacol Sci. 2005;99(5):423-37
references.pmid: 16493184
references.citation: Fundam Clin Pharmacol. 1987;1(6):413-31
references.pmid: 3447930
references.citation: J Pharmacol Exp Ther. 1974 May;189(2):414-22
references.pmid: 4829223
references.citation: Br J Pharmacol. 2011 Nov;164 Suppl 1:S1-324
references.pmid: 22040146
references.citation: Fed Regist. 2005 Oct 20;70(202):61133-4
references.pmid: 16237859
references.citation: Am J Cardiol. 1985 Jan 1;55(1):92-7
references.pmid: 3966404
references.citation: Prog Clin Biol Res. 1989;300:437-40
references.pmid: 2780641
references.citation: Br J Pharmacol. 1991 Jun;103(2):1568-72
references.pmid: 1884111
references.citation: J Physiol. 1998 May 1;508 ( Pt 3):811-23
references.pmid: 9518735
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1977 Dec;301(1):29-37
references.pmid: 600318
references.citation: J Cardiovasc Electrophysiol. 1996 Nov;7(11):1074-81
references.pmid: 8930739
references.citation: Pharmacol Toxicol. 1990 Nov;67(5):420-5
references.pmid: 1982898
references.citation: Jpn Circ J. 2000 Oct;64(10):777-82
references.pmid: 11059619
references.citation: J Pharmacol Toxicol Methods. 2007 Sep-Oct;56(2):159-70
references.pmid: 17604185
references.citation: J Cardiovasc Pharmacol. 1990 Sep;16(3):401-10
references.pmid: 1700210
references.citation: Am J Cardiol. 1984 Feb 27;53(5):41B-51B
references.pmid: 6364769
references.citation: Am J Cardiol. 1984 Feb 27;53(5):26B-29B
references.pmid: 6695816
references.citation: J Pharmacol Sci. 2005;99(5):459-71
references.pmid: 16493187
references.citation: Isr J Med Sci. 1979 Jul;15(7):583-7
references.pmid: 478822
references.citation: Am Heart J. 1988 Sep;116(3):740-6
references.pmid: 3046277
references.citation: Cell Physiol Biochem. 2009;24(5-6):527-36
references.pmid: 19910693
references.citation: Am J Physiol Heart Circ Physiol. 2006 Aug;291(2):H570-80
references.pmid: 16501015
references.citation: J Pharmacol Toxicol Methods. 2006 Sep-Oct;54(2):130-40
references.pmid: 16757186
references.citation: J Pharmacol Sci. 2005;99(5):473-86
references.pmid: 16493188
references.citation: Circ Res. 1999 May 14;84(9):989-98
references.pmid: 10325236
references.citation: Xenobiotica. 1992 Jun;22(6):709-19
references.pmid: 1441594
references.citation: Cardiovasc Res. 1993 May;27(5):861-7
references.pmid: 8348585
references.citation: J Cardiovasc Electrophysiol. 2004 Nov;15(11):1302-9
references.pmid: 15574182
references.citation: Am J Cardiol. 1984 Feb 27;53(5):89B-94B
references.pmid: 6695821
references.citation: Am Heart J. 1982 Apr;103(4 Pt 1):567-9
references.pmid: 7064795
references.citation: Life Sci. 1995;57(21):1887-901
references.pmid: 7475939
references.citation: Circ Res. 1985 Jun;56(6):857-67
references.pmid: 4006095
references.citation: J Gen Physiol. 1985 May;85(5):621-47
references.pmid: 2582076
references.citation: Circ Res. 1974 Feb;34(2):204-13
references.pmid: 4811074
references.citation: J Pharmacol Toxicol Methods. 2010 Jul-Aug;62(1):72-81
references.pmid: 20570746
references.citation: Br J Pharmacol. 2006 Mar;147(6):642-52
references.pmid: 16314852
references.citation: J Cardiovasc Electrophysiol. 2001 Jan;12(1):93-102
references.pmid: 11204092
references.citation: Biopharm Drug Dispos. 1983 Jul-Sep;4(3):249-61
references.pmid: 6626700
references.citation: Pharmacol Toxicol. 1994 Jun;74(6):305-13
references.pmid: 7937562
references.citation: Circ Res. 2000 Nov 24;87(11):1012-8
references.pmid: 11090546
references.citation: Am J Physiol. 1989 Mar;256(3 Pt 1):C549-59
references.pmid: 2538064
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1990 Jun;341(6):565-76
references.pmid: 2168022
references.citation: Circ Res. 1990 Feb;66(2):565-79
references.pmid: 2153473
references.citation: Am J Cardiol. 1986 May 1;57(13):1160-5
references.pmid: 3706170
references.citation: J Pharmacol Exp Ther. 1994 Apr;269(1):66-74
references.pmid: 8169853
references.citation: J Pharmacol Exp Ther. 1991 Jan;256(1):318-24
references.pmid: 1988662
references.citation: Eur J Pharmacol. 2002 Oct 4;452(2):183-92
references.pmid: 12354568
references.citation: J Cardiovasc Pharmacol. 1996 Jan;27(1):42-51
references.pmid: 8656657
references.citation: Am J Cardiol. 1999 Feb 1;83(3):354-9
references.pmid: 10072223
references.citation: J Cardiovasc Pharmacol Ther. 1997 Oct;2(4):273-284
references.pmid: 10684468
references.citation: Eur J Clin Pharmacol. 1973 Dec;6(4):239-44
references.pmid: 4591150
references.citation: Acta Pharmacol Toxicol (Copenh). 1979 Mar;44(3):185-90
references.pmid: 433608
references.citation: Pharmacol Res. 1993 Oct-Nov;28(3):259-64
references.pmid: 8108316
references.citation: J Cardiovasc Pharmacol Ther. 2009 Mar;14(1):28-37
references.pmid: 19246335
references.citation: J Mol Cell Cardiol. 2007 Feb;42(2):357-66
references.pmid: 17178128
references.citation: Chem Biol Interact. 2004 Nov 1;150(1):87-96
references.pmid: 15522263
references.citation: Circulation. 1989 Mar;79(3):674-86
references.pmid: 2917391
references.citation: J Pharmacol Exp Ther. 2000 Aug;294(2):562-70
references.pmid: 10900233
references.citation: J Cardiovasc Pharmacol. 1988;12(5):543-6
references.pmid: 2468053
references.citation: Am J Cardiol. 1981 Dec;48(6):1133-40
references.pmid: 7304461
references.citation: Circulation. 1982 May;65(5):879-85
references.pmid: 7074749
references.citation: J Pharmacol Exp Ther. 1998 May;285(2):672-9
references.pmid: 9580612
references.citation: Can J Physiol Pharmacol. 1985 Dec;63(12):1506-12
references.pmid: 3830350
references.citation: J Pharm Sci. 1973 Mar;62(3):362-75
references.pmid: 4144183
references.citation: Biophys J. 2007 Jun 1;92(11):4121-32
references.pmid: 17307821
references.citation: J Pharmacol Methods. 1989 Nov;22(3):207-17
references.pmid: 2586115
references.citation: Br J Pharmacol. 2002 Jul;136(5):717-29
references.pmid: 12086981
references.citation: Biochim Biophys Acta. 1977 Nov 14;472(3-4):373-98
references.pmid: 334262
references.citation: J Muscle Res Cell Motil. 2005;26(4-5):225-35
references.pmid: 16322911
references.citation: Am Heart J. 1983 Jan;105(1):12-5
references.pmid: 6849225
references.citation: Gen Physiol Biophys. 1999 Oct;18 Spec No:80-5
references.pmid: 10703724
references.citation: J Toxicol Clin Toxicol. 2000;38(6):661-5
references.pmid: 11185975
references.citation: Am Heart J. 1980 Oct;100(4):483-9
references.pmid: 7415936
references.citation: J Cardiovasc Pharmacol. 1993 Feb;21(2):316-22
references.pmid: 7679168
references.citation: J Pharmacol Exp Ther. 2002 Aug;302(2):828-33
references.pmid: 12130750
references.citation: Circ Res. 1988 Feb;62(2):324-37
references.pmid: 2448058
references.citation: Eur J Pharmacol. 2005 Apr 4;512(1):53-60
references.pmid: 15814090
references.citation: J Pharmacokinet Biopharm. 1984 Oct;12(5):495-515
references.pmid: 6520745
references.citation: J Pharmacol Exp Ther. 1990 Jun;253(3):1042-8
references.pmid: 2359015
references.citation: Methods Mol Biol. 2006;337:117-25
references.pmid: 16929943