title: Separation of early afterdepolarizations from arrhythmogenic substrate in the isolated perfused hypokalaemic murine heart through modifiers of calcium homeostasis.
abstract: OBJECTIVE
  We resolved roles for early afterdepolarizations (EADs) and transmural gradients of repolarization in arrhythmogenesis in Langendorff-perfused hypokalaemic murine hearts paced from the right ventricular epicardium.
  
  
  METHODS
  Left ventricular epicardial and endocardial monophasic action potentials (MAPs) and arrhythmogenic tendency were compared in the presence and absence of the L-type Ca(2+) channel blocker nifedipine (10 nm-1 microm) and the calmodulin kinase type II inhibitor KN-93 (2 microm).
  
  
  RESULTS
  All the hypokalaemic hearts studied showed prolonged epicardial and endocardial MAPs, decreased epicardial-endocardial APD(90) difference, EADs, triggered beats and ventricular tachycardia (VT) (n = 6). In all spontaneously beating hearts, 100 (but not 10) nm nifedipine reduced both the incidence of EADs and triggered beats from 66.9 +/- 15.7% to 28.3 +/- 8.7% and episodes of VT from 10.8 +/- 6.3% to 1.2 +/- 0.7% of MAPs (n = 6 hearts, P < 0.05); 1 microm nifedipine abolished all these phenomena (n = 6). In contrast programmed electrical stimulation (PES) still triggered VT in six of six hearts with 0, 10 and 100 nm but not 1 microm nifedipine. 1 microm nifedipine selectively reduced epicardial (from 66.1 +/- 3.4 to 46.2 +/- 2.5 ms) but not endocardial APD(90), thereby restoring DeltaAPD(90) from -5.9 +/- 2.5 to 15.5 +/- 3.2 ms, close to normokalaemic values. KN-93 similarly reduced EADs, triggered beats and VT in spontaneously beating hearts to 29.6 +/- 8.9% and 1.7 +/- 1.1% respectively (n = 6) yet permitted PES-induced VT (n = 6), in the presence of a persistently negative DeltaAPD(90).
  
  
  CONCLUSIONS
  These findings empirically implicate both EADs and triggered beats alongside arrhythmogenic substrate of DeltaAPD(90) in VT pathogenesis at the whole heart level.
authors.affiliation: Physiological Laboratory, University of Cambridge, Cambridge, UK. mjk42@cam.ac.uk
authors.forename: M J
authors.initials: MJ
authors.lastname: Killeen
authors.forename: I S
authors.initials: IS
authors.lastname: Gurung
authors.forename: G
authors.initials: G
authors.lastname: Thomas
authors.forename: K S
authors.initials: KS
authors.lastname: Stokoe
authors.forename: A A
authors.initials: AA
authors.lastname: Grace
authors.forename: C L-H
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004558:Electric Stimulation; D005260:Female; D006706:Homeostasis; D007008:Hypokalemia / Q000378:metabolism*; D008297:Male; D051379:Mice; D009543:Nifedipine / Q000494:pharmacology; D010477:Perfusion; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D002118:Calcium; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D009543:Nifedipine; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides