Early afterdepolarizations produced by d,l-sotalol and clofilium.
BACKGROUND
The roles for L-type calcium current and Na-Ca exchange in early afterdepolarizations (EADs) attending d,l-sotalol and clofilium were examined in canine Purkinje fibers and in enzymatically dispersed myocytes from canine subepicardium.


RESULTS
Spontaneous EADs were compared to EAD formation potentiated by stimulation of Na-Ca exchange and facilitation of ICa-L (Bay K8644). Bay K8644 (10(-8) M) and stimulation of Na-Ca exchange potentiated bradycardia-dependent EADs. Stimulation of Na-Ca exchange in Purkinje fibers pretreated with d,l-sotalol (10(-5) M) and clofilium (10(-7) M) induced EADs at takeoff potentials negative (-63 +/- 4 and -62 +/- 4 mV, respectively) to EADs potentiated by Bay K8644 (10(-8) M) (-33 +/- 2 and -34 +/- 2 mV, respectively, P < 0.05), or EADs induced by Bay K8644 alone (10(-6) M) (-31 +/- 5 mV). In myocytes, Bay K8644 (10(-8) M) potentiated EADs in d,l-sotalol- (10(-6) to 10(-4) M) or clofilium-treated (10(-9) to 10(-7) M) cells at reduced potentials (-10 +/- 3 and -10 +/- 4 mV, respectively) compared to EADs elicited by clofilium or d,l-sotalol alone (-25 +/- 3 and -24 +/- 3 mV, respectively), or stimulation of Na-Ca exchange in the presence of d,l-sotalol or clofilium (-26 +/- 4 and -26 +/- 4 mV, respectively). Spontaneous EADs or EADs elicited by stimulation of Na-Ca exchange coincident with drug treatment were suppressed by increasing Ca02+ but were not suppressed by nifedipine (10(-7) M).


CONCLUSIONS
EADs elicited by d,l-sotalol and clofilium in canine Purkinje tissue and epicardial myocytes are dependent upon Na-Ca exchange rather than ICa-L "window current."
Patterson
E
E
Department of Pharmacology, College of Medicine, University of Oklahoma Health, Sciences Center, Oklahoma City, USA.
Scherlag
B J
BJ
Lazzara
R
R
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D010496:Pericardium / Q000166:cytology; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger; D013015:Sotalol / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002352:Carrier Proteins; D000644:Quaternary Ammonium Compounds; D019831:Sodium-Calcium Exchanger; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C022799:clofilium; D012964:Sodium; D013015:Sotalol; D009543:Nifedipine; D002118:Calcium