Kodama I, Anno T, Sudo Y, Satake N, Shibata S
Department of Pharmacology, University of Hawaii, School of Medicine, Honolulu 96822.
Cardiovasc Res. 1989 May;23(5):369-77. doi: 10.1093/cvr/23.5.369.
Effects of the cardiotonic agent FK664, 6-(3, 4-dimethoxy-phenyl)-1-ethyl-4-mesitylimino-3-methyl-3,4-dihydro-2 (1H)-pyrimidone, on isolated guinea pig ventricular muscles and rabbit sinus node pacemaker cells were studied using micro-electrode techniques. In ventricular muscles driven at 0.5-1.0 Hz, FK664 above 3 mumol.litre-1 caused an increase in contractile force and a shortening of time to peak tension. This positive inotropic effect of FK664 was accompanied by a slight elevation of the early plateau phase of the action potential, while other action potential variables were unaffected. The change in contractile force induced by FK664 was abolished in a low Ca2+ medium (0.12 mmol.litre-1) or by treatment with ryanodine (2 mumol.litre-1), whereas it was relatively well preserved in the preparations pretreated with nefedipine (1 mumol.litre-1). The slow action potentials induced by isoprenaline (0.3 mumol.litre-1) in high K+ medium (30 mmol.litre-1) and the slow inward current measured by single sucrose gap voltage clamp at a holding potential of -40 mV were unaffected by FK664. In sinus node pacemaker cells, FK664 (1-10 mumol.litre-1) caused a dose dependent acceleration of phase 4 depolarisation and a shortening of spontaneous firing cycle length. This positive chronotropic effect of FK664 was markedly inhibited in a low Ca2+ medium (0.3 mmol.litre-1). These findings suggest that FK664 has positive inotropic and chronotropic effects on the heart, due to an enhancement of transsarcolemmal calcium influx through the low threshold, dihydropyridine insensitive Ca2+ channel population.
强心剂FK664，即6-(3,4-二甲氧基苯基)-1-乙基-4-均三甲苯基亚氨基-3-甲基-3,4-二氢-2(1H)-嘧啶酮，对豚鼠离体心室肌和兔窦房结起搏细胞的作用采用微电极技术进行了研究。在以0.5 - 1.0 Hz驱动的心室肌中，浓度高于3 μmol·L⁻¹的FK664可使收缩力增加，并缩短达到峰值张力的时间。FK664的这种正性肌力作用伴随着动作电位早期平台期的轻微升高，而其他动作电位变量未受影响。FK664引起的收缩力变化在低钙培养基（0.12 mmol·L⁻¹）中或用ryanodine（2 μmol·L⁻¹）处理后被消除，而在用硝苯地平（1 μmol·L⁻¹）预处理的制剂中相对保留较好。异丙肾上腺素（0.3 μmol·L⁻¹）在高钾培养基（30 mmol·L⁻¹）中诱导的慢动作电位以及在 - 40 mV的钳制电位下通过单蔗糖间隙电压钳测量的慢内向电流不受FK664影响。在窦房结起搏细胞中，FK664（1 - 10 μmol·L⁻¹）引起4期去极化的剂量依赖性加速和自发放电周期长度的缩短。FK664的这种正性变时作用在低钙培养基（0.3 mmol·L⁻¹）中明显受到抑制。这些发现表明，FK664对心脏具有正性肌力和正性变时作用，这是由于通过低阈值、对二氢吡啶不敏感的钙通道群体增强了跨肌膜钙内流所致。
