2APB- and JTV519(K201)-sensitive micro Ca2+ waves in arrhythmogenic Purkinje cells that survive in infarcted canine heart.

OBJECTIVES/
BACKGROUND: Studies from several laboratories have implicated intracellular Ca(2+) dynamics in the modulation of electrical activity. We have reported that abnormal Ca(2+) wave activity is the underlying cause of afterdepolarization-induced electrical activity in subendocardial Purkinje cells that survive in the 48-hour infarcted canine heart. These cells form the focus of arrhythmias at this time postcoronary artery occlusion.
METHODS: We studied the effects of agonists and antagonists on the abnormal Ca(2+) release activity of Purkinje cell aggregates dispersed from the subendocardium 48 hours postcoronary artery occlusion (IZPCs). Studies were completed using epifluorescent microscopy of Fluo-3 loaded Purkinje cells.
RESULTS: Similar to our previous report, highly frequent traveling micro Ca(2+) transients (muCaiTs) and cell-wide Ca(2+) waves were seen in IZPCs in the absence of any drug. Isoproterenol (ISO) increased muCaiTs and cell-wide Ca(2+) waves in Purkinje cells dispersed from the normal heart (NZPCs). In IZPCs, ISO increased cell-wide wave frequency but had no effect on the already highly frequent micro Ca(2+) wave transient activity, suggesting that ISO lowers the threshold of cell-wide generators responding to micro Ca(2+) transients. Drugs that block inward sodium or calcium currents (verapamil, tetrodotoxin) had no effect on Ca(2+) activity in Purkinje cells. Antagonists of intracellular Ca(2+) release channels [ryanodine, JTV519(K201)] greatly suppressed spontaneous Ca(2+) release events in IZPCs. 2APB, an agent that blocks IP(3) receptors, greatly reduced the frequency of Ca(2+) events in IZPCs.
CONCLUSIONS: In arrhythmogenic Purkinje cells that survive in the infarcted heart, agents that block or inhibit intracellular Ca(2+) release channel activity reduced Ca(2+) waves and could be antiarrhythmic.