Developmental changes in IKr and IKs contribute to age-related expression of dofetilide effects on repolarization and proarrhythmia.
OBJECTIVE
Clinical and experimental studies suggest that immature hearts are as or more sensitive than adult hearts to adverse effects of I(Kr) blocking drugs. We hypothesized that age-dependent changes in I(Kr) and I(Ks) contribute to the different repolarization reserves and proarrhythmic effects of I(Kr) blockers in the young and adult heart.


METHODS
Dogs aged 1-150 days and adults were used to study (1) proarrhythmic effects in situ of the I(Kr) blocker dofetilide; (2) dofetilide effects on action potential duration (APD) recorded with microelectrodes from left ventricular (LV) slabs; (3) I(Kr) and I(Ks) in single LV myocytes using whole-cell voltage clamp.


RESULTS
In situ, dofetilide-induced proarrhythmia occurred in 40% of adults, 86% of young (20-150 day) dogs and 0% of neonatal (1-19 day) dogs (P<0.05). Isolated tissue experiments showed no transmural gradient for repolarization from neonate through 3 months of age, after which the gradient increased through adulthood. In the presence of dofetilide, the greatest APD prolongation occurred in neonates. Yet, transmural dispersion did not increase in neonates but significantly increased in young and adults. Dofetilide-induced early after depolarization (EAD) incidence was 23% in adults, 59% in young and 8% in neonates (P<0.05). I(Kr) but not I(Ks) was expressed at <30 days, whereas both currents were present in adult myocardium.


CONCLUSIONS
Our data suggest that a lack of I(Ks) results in a greater dependence on I(Kr) for repolarization in neonates and is associated with exaggerated effects of I(Kr)-blockade on APD. However, APD prolongation alone is insufficient for expression of proarrhythmia, which also requires transmural dispersion of repolarization and EADs. The extent to which APD prolongation, transmural dispersion and EADs are manifested at various ages in the absence and presence of I(Kr) blocking drugs appears to be the ultimate determinant of proarrhythmia.
Obreztchikova
Maria N
MN
Department of Pharmacology, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Sosunov
Eugene A
EA
Plotnikov
Alexei
A
Anyukhovsky
Evgeny P
EP
Gainullin
Ravil Z
RZ
Danilo
Peter
P
Yeom
Zi-Ho
ZH
Robinson
Richard B
RB
Rosen
Michael R
MR
D000200:Action Potentials / Q000187:drug effects; D000375:Aging / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D004285:Dogs; D005260:Female; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*
D010627:Phenethylamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013449:Sulfonamides; C063533:dofetilide