Obreztchikova Maria N, Sosunov Eugene A, Plotnikov Alexei, Anyukhovsky Evgeny P, Gainullin Ravil Z, Danilo Peter, Yeom Zi-Ho, Robinson Richard B, Rosen Michael R
Department of Pharmacology, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Cardiovasc Res. 2003 Aug 1;59(2):339-50. doi: 10.1016/s0008-6363(03)00360-2.
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.
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.
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.
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.
临床和实验研究表明，未成熟心脏对I(Kr)阻断药物的不良反应与成年心脏一样敏感或更敏感。我们推测，I(Kr)和I(Ks)随年龄的变化导致了未成熟和成年心脏中不同的复极储备以及I(Kr)阻断剂的促心律失常作用。
使用1至150日龄的犬和成年犬来研究：(1) I(Kr)阻断剂多非利特的原位促心律失常作用；(2) 多非利特对用微电极从左心室切片记录的动作电位时程(APD)的影响；(3) 使用全细胞膜片钳记录单个左心室心肌细胞中的I(Kr)和I(Ks)。
在原位实验中，多非利特诱发的心律失常在40%的成年犬、86%的幼龄（20至150日龄）犬中出现，而在新生（1至19日龄）犬中未出现（P<0.05）。离体组织实验表明，从新生犬到3月龄犬，复极不存在跨壁梯度，此后该梯度在成年期逐渐增加。在多非利特存在的情况下，新生犬的APD延长最为明显。然而，新生犬的跨壁离散度并未增加，而幼龄犬和成年犬则显著增加。多非利特诱发的早期后除极(EAD)发生率在成年犬中为23%，在幼龄犬中为59%，在新生犬中为8%（P<0.05）。I(Kr)在30日龄前表达，而I(Ks)不表达，两种电流在成年心肌中均存在。
我们的数据表明，I(Ks)的缺乏导致新生犬在复极过程中对I(Kr)的依赖性更强，并且与I(Kr)阻断对APD的过度影响相关。然而，单纯的APD延长不足以引发心律失常，还需要复极的跨壁离散和EADs。在不存在和存在I(Kr)阻断药物的情况下，不同年龄阶段APD延长、跨壁离散和EADs的表现程度似乎是心律失常的最终决定因素。
