CA ANTAGONISTS AND CA CHANNELS

长期目标和具体目标是阐明机制 Ca拮抗剂通过其对Ca通道发挥作用。 在 许多易兴奋细胞，钙离子的进入可被维拉帕米抑制， D-600、地尔硫卓和二氢吡啶化合物如硝苯地平和 尼群地平 这些药物通常被称为“钙拮抗剂”或“钙通道 阻断剂”，并且在临床上是重要的，因为它们发挥抗肿瘤作用， 和抗心绞痛作用。 治疗相关的目标，这些 试剂是心肌纤维细胞膜中的Ca通道， 血管平滑肌（特别是冠状动脉）。 之甚少 了解钙拮抗剂如何与钙离子相互作用并阻断钙离子通道。 渠道 关于其作用机制的一个假设是， 通道必须在它们被这些化合物阻断之前打开。 现在，对这些药物作用机制的理解取得了重大进展。 通过使用膜片钳技术 记录，这使我们能够直接获得有关 单通道水平的药物-通道相互作用。 在拟议的研究中，成年豚鼠的分离心室细胞 猪心脏和培养的鸡心肌细胞将被用作材料， 膜片钳技术适用于它们。 的阻断作用 以维拉帕米为代表的三大类有机钙拮抗剂 或D-600、地尔硫卓和尼群地平将在全细胞上进行检查 膜片钳技术的变化。 在这些实验中， 阻滞的频率（使用）依赖性、电压依赖性和剂量反应 药物诱导的钙电流动力学的可能变化将是 研究了 这些将为我们提供“宏观”的图景 通过单通道获得的“微观”效应 记录可以比较。 将通过以下方式分析药物作用模式： 单通道录音 代理人预计将相互作用 优先使用开放的渠道。 分析是基于测量的 的开放时间，阻断时间，突发周期，和电压依赖性， 块 这项研究预计将提供有用的信息， 钙拮抗剂的临床应用。

The long-term objectives and specific aims are to elucidate the mechanisms by which Ca antagonistic agents exert their effects on Ca channels. In many excitable cells, the entry of Ca ions can be inhibited by verapamil, D-600, diltiazem and dihydropyridine compounds such as nifedipine and nitrendipine. These drugs are often called "Ca antagonists" or "Ca channel blockers" and are clinically important because they exert antiarrhythmic and antianginal actions. The therapeutically relevant targets for these agents are Ca channels in the cell membrane of myocardial fibers and vascular smooth muscles (particularly of the coronary artery). Little is known about how the Ca antagonistic agents interact with and block the Ca channels. One hypothesis concerning their mechanism of action is that the channels must open before they can be blocked by these compounds. Significant advances in understanding the mechanism of these drugs are now possible through the use of the patch clamp technique for single channel recording, which enables us to directly obtain information about drug-channel interactions at the single channel level. In the proposed research, isolated ventricular cells of the adult guinea pig heart and cultured chick myocytes will be used as the materials since the patch clamp technique is applicable to them. The blocking effects of the three major classes of organic Ca antagonists, represented by verapamil or D-600, diltiazem and nitrendipine will be examined on the whole cell variation of the patch clamp technique. In these experiments, the frequency (use) dependence, voltage dependence and dose-response of block and possible change in the kinetics of Ca current induced by drugs will be investigated. These will provide us with the picture of "macroscopic" effects with which "microscopic" effects obtained by single channel recording can be compared. The mode of the drug action will be analyzed by the single channel recording. The agents are expected to interact preferentially with open channels. The analyses are based on measurement of the open time, blocked time, the burst period, and voltage dependence of block. This research is expected to provide useful information about the clinical application of Ca antagonists.