2APB- and JTV519(K201)-sensitive micro Ca2+ waves in arrhythmogenic Purkinje cells that survive in infarcted canine heart.
OBJECTIVE
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.
Boyden
Penelope A
PA
Department of Pharmacology, New York, New York, USA. pab4@columbia.edu
Dun
Wen
W
Barbhaiya
Chirag
C
Ter Keurs
Henk E D J
HE
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000814:Aniline Compounds; D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology*; D004396:Coloring Agents; D004285:Dogs; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008856:Microscopy, Fluorescence; D009203:Myocardial Infarction / Q000378:metabolism*; D011689:Purkinje Cells / Q000378:metabolism*; D013841:Thiazepines / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology; D014966:Xanthenes
D000318:Adrenergic beta-Agonists; D000814:Aniline Compounds; D001896:Boron Compounds; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004396:Coloring Agents; D013841:Thiazepines; D014966:Xanthenes; C109183:K201 compound; C059715:Fluo-3; D014700:Verapamil; C109986:2-aminoethoxydiphenyl borate; D007545:Isoproterenol; D002118:Calcium