Thomas G, Gross R, Schramm M
J Cardiovasc Pharmacol. 1984 Nov-Dec;6(6):1170-6.
BAY K 8644, a dihydropyridine of the nifedipine type, was shown to increase coronary resistance and to enhance myocardial contractility (Schramm et al., Nature 1983;303:535-7), in contrast to the well-known vasodilating and negative inotropic effects of the "classical" calcium channel blockers. In the isolated perfused guinea pig heart at high concentrations (greater than 3 microM), however, the coronary constricting and positive inotropic effects of BAY K 8644 progressively reverse until the drug has a negative inotropic effect and decreases coronary resistance, thus mimicking the effects of the "classical" calcium antagonists. On the other hand, in the same experimental model, calcium antagonists like nifedipine, nitrendipine, and nicardipine are shown to exert a small but definite positive inotropic effect at low concentrations, indicating a calcium agonistic action at those concentrations. To explain the pharmacological effects of BAY K 8644 and the calcium channel blockers of the dihydropyridine type, a model is proposed that suggests the existence of two dihydropyridine binding sites per channel. According to this model, it depends on the chemical structure of the respective dihydropyridine whether, after occupation of the first site, which increases the calcium influx through the channel, the occupation of the second site is unimpaired, turning the channel to one with low calcium permeability; or whether occupation of the second site is hindered, leaving the channel in the high conductance state.
BAY K 8644是一种硝苯地平类二氢吡啶，与“经典”钙通道阻滞剂众所周知的血管舒张和负性肌力作用相反，它能增加冠状动脉阻力并增强心肌收缩力（施拉姆等人，《自然》，1983年；303:535 - 537）。然而，在高浓度（大于3微摩尔）的离体灌注豚鼠心脏中，BAY K 8644的冠状动脉收缩和正性肌力作用会逐渐逆转，直到该药物产生负性肌力作用并降低冠状动脉阻力，从而模拟“经典”钙拮抗剂的作用。另一方面，在相同的实验模型中，硝苯地平、尼群地平和尼卡地平等钙拮抗剂在低浓度时显示出微小但明确的正性肌力作用，表明在这些浓度下存在钙激动作用。为了解释BAY K 8644和二氢吡啶类钙通道阻滞剂的药理作用，提出了一个模型，该模型表明每个通道存在两个二氢吡啶结合位点。根据这个模型，取决于各自二氢吡啶的化学结构，在占据第一个位点（该位点会增加通过通道的钙内流）后，第二个位点的占据是否不受影响，从而使通道转变为低钙通透性的通道；或者第二个位点的占据是否受到阻碍，使通道处于高电导状态。
