Anti-arrhythmic effects of cyclopiazonic acid in Langendorff-perfused murine hearts.
We investigated the effects of reducing sarcoplasmic reticular (SR) Ca(2+) stores using the Ca(2+)-ATPase inhibitor cyclopiazonic acid (CPA) in Langendorff-perfused mouse hearts exposed to different pro-arrhythmic agents all known to produce Ca(2+)-mediated arrhythmogenesis. CPA (100 and 150 nM) produced progressive (beginning over approximately 1 min) and significant (P<0.0001) reductions in peak amplitudes of Ca(2+) transients evoked by regular stimulation in isolated Fluo-3 loaded myocytes from F/F(0)=3.2+/-0.16 (n=12 cells) to 1.62+/-0.012 (n=6 cells) and 1.53+/-0.06 (n=12 cells), respectively, consistent with previous reports describing reductions of store Ca(2+) in other cell systems. The corresponding effects of CPA were then examined in intact hearts exposed to isoproterenol (100 nM), elevated extracellular [Ca(2+)] (5mM) and caffeine (1mM). All three agents produced ventricular tachycardia either when added alone or simultaneously with CPA during programmed electrical stimulation. However, arrhythmogenicity was not observed when such agents were added approximately 10 min after introduction of CPA. CPA thus antagonized this Ca(2+)-mediated arrhythmogenesis but only under circumstances of SR Ca(2+) depletion. These alterations in arrhythmogenic tendency took place despite an absence of alterations in electrogram and monophasic action potential characteristics. This was in sharp contrast to previous observations in murine, DeltaKPQ-Scn5a (LQT3) and KCNE1(-/-) (LQT5), systems where re-entry has been implicated in arrhythmogenesis.
Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
Nina S
NS
Ghais
Yanmin
Y
Zhang
Bina
B
Mistry
Andrew A
AA
Grace
Christopher L-H
CL
Huang
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology; D002118:Calcium / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010477:Perfusion
D000889:Anti-Arrhythmia Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D000252:Calcium-Transporting ATPases; D002118:Calcium; C000543:cyclopiazonic acid