Mészáros J, Ryder K O, Hart G
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, United Kingdom.
Am J Physiol. 1996 Dec;271(6 Pt 2):H2360-7. doi: 10.1152/ajpheart.1996.271.6.H2360.
We have demonstrated that a daily injection of isoproterenol (5 mg/kg ip) for 7 days induces a 30% increment in heart weight-to-body weight ratio and prolongs the action potential duration (APD) in male Wistar rats. The underlying mechanism of the prolonged APD was investigated in this model of hypertrophy by measuring the transient outward potassium current (Ito) in left ventricular myocytes of the rat with whole cell voltage-clamp techniques. Cell membrane capacitance was increased by 39%: 122 +/- 3 (n = 23) and 171 +/- 5 (SE) pF (n = 20) in control and hypertrophy, respectively (P < 0.001). Ito was evoked in sodium-free solutions containing 0.5 mM Ca2+ and 2 mM Co2+ by step depolarizations from a holding potential of -80 mV. The amplitude of the 4-aminopyridine-sensitive Ito (at 70 mV) was reduced by 28% in hypertrophy: 3.2 +/- 0.3 (n = 23) and 2.3 +/- 0.4 (SE) nA (n = 20) in control and hypertrophy, respectively (P < 0.05). When normalized for cell capacitance, the reduction was much larger: 26.4 +/- 2.5 and 13.1 +/- 1.8 pA/pF in control and hypertrophy, respectively (P < 0.001). The voltage dependence of Ito was similar in both cell types. No change was observed in the steady-state activation and inactivation kinetics in the two groups, nor was there a change in the time dependence of inactivation. The recovery from inactivation of Ito when fitted with a monoexponential function was not changed significantly in hypertrophy: time constants = 8.2 +/- 0.4 (n = 13) and 8.3 +/- 0.3 ms (n = 12) in control and hypertrophy, respectively. These results show that Ito density is decreased in catecholamine-induced cardiac hypertrophy, but current kinetics are not affected. The reduced Ito density may underlie the prolongation of APD in this model of hypertrophy.
我们已经证明，每天腹腔注射异丙肾上腺素（5毫克/千克），连续7天，可使雄性Wistar大鼠的心脏重量与体重之比增加30%，并延长动作电位时程（APD）。通过采用全细胞电压钳技术测量大鼠左心室肌细胞的瞬时外向钾电流（Ito），在这种肥大模型中研究了APD延长的潜在机制。细胞膜电容增加了39%：对照组为122±3（n = 23）皮法，肥大组为171±5（标准误）皮法（n = 20）（P < 0.001）。在含有0.5毫摩尔/升Ca2+和2毫摩尔/升Co2+的无钠溶液中，通过从-80毫伏的保持电位进行阶跃去极化来诱发Ito。肥大组中对4-氨基吡啶敏感的Ito（在70毫伏时）幅度降低了28%：对照组为3.2±0.3（n = 23）纳安，肥大组为2.3±0.4（标准误）纳安（n = 20）（P < 0.05）。以细胞电容进行归一化后，降低幅度更大：对照组为26.4±2.5皮安/皮法，肥大组为13.1±1.8皮安/皮法（P < 0.001）。两种细胞类型中Ito的电压依赖性相似。两组的稳态激活和失活动力学均未观察到变化，失活的时间依赖性也没有变化。当用单指数函数拟合时，肥大组中Ito从失活状态恢复的情况没有显著改变：对照组的时间常数为8.2±0.4（n = 13）毫秒，肥大组为8.3±0.3毫秒（n = 12）。这些结果表明，在儿茶酚胺诱导的心脏肥大中Ito密度降低，但电流动力学不受影响。Ito密度降低可能是该肥大模型中APD延长的基础。
