Window Ca2+ current and its modulation by Ca2+ release in hypertrophied cardiac myocytes from dogs with chronic atrioventricular block.
Torsades de pointes (TdP) ventricular tachycardia typically occurs in the setting of early afterdepolarizations; it contributes to arrhythmias and sudden death in congenital and acquired heart disease. Window L-type Ca2+ current (ICaL) has a central role in the arrhythmogenesis and may be particularly important under beta-adrenergic stimulation. We studied the properties of ICaL in myocytes from the dog with chronic atrioventricular block (cAVB) that has cardiac hypertrophy and an increased susceptibility to TdP. Peak ICaL densities at baseline (K+ - and Na+ -free solutions, 10 mmol l(-1) [EGTA]pip) in cAVB were comparable to control, but inactivation was shifted to the right, resulting in a larger window current area in cAVB. Under beta-adrenergic stimulation, the window current area was increased and shifted to the left, but less so in cAVB (maximum at -27 mV, versus -32 mV in control). ICaL during a step to -35 mV showed a transient reduction immediately after the peak. Test steps to 0 mV, simultaneous recording of [Ca2+]i and manipulation of sarcoplasmic reticulum (SR) Ca2+ release showed that this resulted from inhibition and fast recovery of ICaL with SR Ca2+ release. The extent of this dynamic modulation was larger in cAVB than in control (23 +/- 2% of the initially available current, versus 13 +/- 3%; P<0.05). Early afterdepolarizations (EADs) in cAVB myocytes under beta-adrenergic stimulation typically occurred in the window current voltage range and after decline of [Ca2+]i. In conclusion, in cAVB, the larger window current, its rightward shift and enhanced dynamic modulation by SR Ca2+ release may contribute to an increased incidence of EADs in cAVB under beta-adrenergic stimulation.
Antoons
Gudrun
G
Laboratory of Experimental Cardiology, University of Leuven, Leuven, Belgium.
Volders
Paul G A
PG
Stankovicova
Tania
T
Bito
Virginie
V
Stengl
Milan
M
Vos
Marc A
MA
Sipido
Karin R
KR
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002021:Buffers; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006327:Heart Block / Q000378:metabolism* / Q000473:pathology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D016171:Torsades de Pointes / Q000378:metabolism / Q000473:pathology
D000318:Adrenergic beta-Agonists; D002021:Buffers; D020746:Calcium Channels, L-Type; D007545:Isoproterenol; D002118:Calcium