Marsh J D, Dionne M A, Chiu M, Smith T W
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
J Mol Cell Cardiol. 1988 Dec;20(12):1141-50. doi: 10.1016/0022-2828(88)90594-9.
To define the cellular mechanism of action of a dihydropyridine Ca channel antagonist in an experimental model system devoid of neural influences and reflex effects, we studied the actions of RS93522 on cultured vascular smooth muscle cells and on cultured chick embryo ventricular cells. 45Ca uptake by monolayer cultures of vascular smooth muscle cells was inhibited in a concentration-dependent manner. The IC50 for this effect was 10 nM, similar to that for nifedipine (7 nM) in the same system. 10(-6) M RS93522 inhibited 45Ca uptake more fully than 10(-6) M nifedipine (P less than 0.05). Using an optical-video system, the effect of RS93522 on amplitude of contraction of spontaneously beating cultured ventricular cells was studied. Amplitude of contraction was inhibited with IC50 = 7.9 x 10(-8)M. 45Ca uptake in myocytes was depressed by 15% at 5 min. RS93522 had the additional property of inhibiting phosphodiesterase activity in myocardial homogenates with IC50 = 1.6 x 10(-5)M; the potency and efficacy of phosphodiesterase inhibition was similar to that for milrinone in the same system. As expected of Ca channel antagonists, it has a negative inotropic effect on cultured myocardial cells. The compound also has phosphodiesterase inhibitory activity that possibly may potentiate vasodilatation and ameliorate, in part, negative inotropic effects. Thus, RS93522 has two distinct pharmacodynamic effects in myocytes and is a potent calcium channel blocker.
为了在一个没有神经影响和反射效应的实验模型系统中确定二氢吡啶钙通道拮抗剂的细胞作用机制，我们研究了RS93522对培养的血管平滑肌细胞和培养的鸡胚心室细胞的作用。血管平滑肌细胞单层培养物对45Ca的摄取以浓度依赖的方式受到抑制。这种作用的IC50为10 nM，与同一系统中硝苯地平的IC50（7 nM）相似。10(-6) M的RS93522比10(-6) M的硝苯地平更完全地抑制45Ca摄取（P<0.05）。使用光学视频系统，研究了RS93522对自发搏动的培养心室细胞收缩幅度的影响。收缩幅度受到抑制，IC50 = 7.9 x 10(-8)M。5分钟时，心肌细胞对45Ca的摄取减少了15%。RS93522还具有抑制心肌匀浆中磷酸二酯酶活性的特性，IC50 = 1.6 x 10(-5)M；磷酸二酯酶抑制的效力和效果与同一系统中米力农的相似。正如钙通道拮抗剂所预期的那样，它对培养的心肌细胞有负性肌力作用。该化合物还具有磷酸二酯酶抑制活性，可能会增强血管舒张并部分改善负性肌力作用。因此，RS93522在心肌细胞中有两种不同的药效学作用，是一种有效的钙通道阻滞剂。
