title: Hypotonic-induced stretch counteracts the efficacy of the class III antiarrhythmic agent E-4031 in guinea pig myocytes.
abstract: OBJECTIVE
  The aim was to determine the effect and mechanisms by which myocyte stretch interacts with the prolongation of action potential duration (APD) by the class III antiarrhythmic agent E-4031.
  
  
  METHODS
  Action potentials and whole-cell currents were measured in isolated guinea pig ventricular myocytes with a patch clamp procedure during perfusion of normotonic, normotonic with addition of E-4031, and hypotonic plus E-4031 solutions.
  
  
  RESULTS
  Cell swelling leading to membrane stretch of myocytes in the whole-cell recording configuration occurred with hypotonic solution perfusion. APD, prolonged by E-4031, was reduced to less than control value with hypotonic-induced stretch. Evaluation of whole-cell currents after hypotonic-induced stretch revealed no significant changes in the L-type Ca2+ current, inward rectifier K+ current or the rapid component of the delayed rectifier K+ current. The slow component of the delayed rectifier K+ current (IKs) was upregulated and a stretch-induced CI- current was activated in hypotonic solutions. The hypotonic-induced modulation of these currents was not effected by protein kinase A or C inhibition.
  
  
  CONCLUSIONS
  Hypotonic-induced stretch shortens APD and counteracts the effects of E-4031. This APD shortening is secondary to upregulation of IKs and activation of a stretch-induced Cl- current.
authors.affiliation: Department of Medicine, Oregon Health Sciences University, Portland 97201-3098, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Groh
authors.forename: K J
authors.initials: KJ
authors.lastname: Gibson
authors.forename: J G
authors.initials: JG
authors.lastname: Maylie
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D018118:Chloride Channels / Q000187:drug effects; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D007038:Hypotonic Solutions / Q000494:pharmacology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D015220:Calcium Channels; D018118:Chloride Channels; D007038:Hypotonic Solutions; D010880:Piperidines; D015221:Potassium Channels; D011725:Pyridines; C063968:E 4031