Anti-arrhythmic effects of cyclopiazonic acid in Langendorff-perfused murine hearts

作者：Ghais Nina S; Zhang Yanmin; Mistry Bina; Grace Andrew A; Huang Christopher L H^*

来源：Progress in Biophysics and Molecular Biology, 2008, 98(2-3): 281-288.

DOI：10.1016/j.pbiomolbio.2009.01.004

• Sarco-endoplasmic Ca(2+)-ATPase
• Calcium stores
• Cyclopiazonic acid
• Programmed electrical stimulation
• Monophasic action potentials
• Ventricular arrhythmogenesis

We investigated the effects of reducing sarcoplasmic reticular (SR) Ca2+ stores using the Ca(2+)-ATPase inhibitor cyclopiazonic acid (CPA) in Langendorff-perfused mouse hearts expose to different pro-arrhythmic agents all known to produce Ca(2+)-mediated arrhythmogenesis. CPA (100 and 150 nM) produced progressive (beginning over similar to 1 min) and significant (P<0.0001) reductions in peak amplitudes of Ca(2+) transients evoked by regular stimulation in isolate 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+)] (5 mM) and caffeine (1 mM). 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 similar to 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 ail absence of alterations in electrogrann and monophasic action potential characteristics. This was in sharp contrast to Previous observations in murine, Delta KPQ-Scn5a (LQT3) and KCNE1(-1) (LQT5), systems where re-entry has been implicated in arrhythmogenesis.

• 出版日期2008-11
• 单位西安交通大学