Hypotonic-induced stretch counteracts the efficacy of the class III antiarrhythmic agent E-4031 in guinea pig myocytes.
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.
Groh
W J
WJ
Department of Medicine, Oregon Health Sciences University, Portland 97201-3098, USA.
Gibson
K J
KJ
Maylie
J G
JG
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*
D000889:Anti-Arrhythmia Agents; D015220:Calcium Channels; D018118:Chloride Channels; D007038:Hypotonic Solutions; D010880:Piperidines; D015221:Potassium Channels; D011725:Pyridines; C063968:E 4031