L-type calcium current reactivation contributes to arrhythmogenesis associated with action potential triangulation.
BACKGROUND
The morphology of the mammalian cardiac action potential (AP) is an important factor in the susceptibility to drug-induced early afterdepolarizations (EADs) that may initiate torsade de pointes (TdP). AP triangulation has been shown to be an important predictor of drug-induced TdP.


RESULTS
APs from guinea pig and rabbit left ventricular single myocytes were recorded using a microelectrode-recording technique. I(Ca-L) currents were recorded in ventricular myocytes of guinea pig and rabbit using patch-clamping technique. At a stimulus frequency of 0.5 Hz, guinea pig ventricular myocytes displayed a square-like AP, whereas rabbit ventricular myocytes exhibited a triangle-like AP. Dofetilide-induced EADs were observed only in rabbit ventricular myocytes. Under the guinea pig AP clamping condition, the normalized I(Ca-L) instant reactivation currents in guinea pig and rabbit myocytes at voltages of -40 mV were 0.13 +/- 0.01 and 0.14 +/- 0.01, respectively. However, when rabbit AP served as the first clamping voltage, the normalized I(Ca-L) reactivation currents at -40 mV in guinea pig and rabbit myocytes were 0.20 +/- 0.01, 0.21 +/- 0.01, respectively, indicating that the I(Ca-L) recovery from inactivation in the rabbit triangular AP condition was significantly faster than in the guinea pig square AP condition. Comparison of the voltage clamp using the triangular waveform with the square waveform further confirmed that triangulation accelerates I(Ca-L) recovery from inactivation.


CONCLUSIONS
In rabbit ventricular myocardium, AP triangulation accelerates I(Ca-L) channel recovery from inactivation, leading to instability of the cell membrane potential during repolarization, which is capable of initiating TdP.
Guo
Donglin
D
Main Line Health Heart Center, Wynnewood, Pennsylvania 19096, USA. guod@mlhs.org
Zhao
Xiaojing
X
Wu
Ying
Y
Liu
Tengxian
T
Kowey
Peter R
PR
Yan
Gan-Xin
GX
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D006168:Guinea Pigs; D006827:Hydantoins; D048289:Imidazolidines / Q000494:pharmacology; D066298:In Vitro Techniques; D032383:Myocytes, Cardiac / Q000187:drug effects*; D009529:Nicardipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D006827:Hydantoins; D048289:Imidazolidines; D010627:Phenethylamines; D010879:Piperazines; D013449:Sulfonamides; C086123:azimilide; D009529:Nicardipine; C063533:dofetilide