CA ANTAGONISTS AND CA CHANNELS

CA 拮抗剂和 CA 通道

• 批准号: 3343946
• 负责人: JAY Z YEH
• 金额: $ 4.97万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-05-01 至 1988-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3343946
• 关键词: angina pectoris; antiarrhythmic agent; calcium channel blockers; cardiotonic agents; cell membrane; coronary artery; drug interactions; drug metabolism; heart disorder chemotherapy; heart pharmacology; ion transport; membrane permeability; myocardium; myofibrils; nifedipine; tissue /cell culture; vascular smooth muscle; verapamil

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.

长期目标和具体目标是阐明这些机制 钙拮抗剂通过何种途径对钙通道产生作用。在……里面 许多可兴奋的细胞，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”。 阻滞剂“，临床上很重要，因为它们发挥抗心律失常的作用 以及抗心绞痛的作用。这些药物的治疗相关靶点 药物是心肌纤维细胞膜上的钙通道， 血管的平滑肌肉(尤其是冠状动脉的)。小才是 了解钙拮抗剂如何与钙离子相互作用并阻断钙离子 频道。关于它们的作用机制的一个假设是， 通道必须打开，然后才能被这些化合物阻断。 在了解这些药物的机制方面取得了重大进展 可通过使用膜片钳技术实现单通道 记录，这使我们能够直接获得关于 单通道水平上的药物-通道相互作用。 在拟议的研究中，成年豚鼠的分离的心室细胞 猪心和培养的鸡心肌细胞将作为材料，因为 膜片钳技术适用于它们。的阻隔效应 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在整个细胞上进行检查 膜片钳技术的变异。在这些实验中， 阻滞剂的频率(使用)依赖性、电压依赖性和剂量效应 而药物诱导的钙电流动力学的可能变化将是 调查过了。这些将为我们提供一幅“宏观”的图景。 单通道获得“微观”效果的效果 录音是可以比较的。药物作用的模式将通过以下方式分析 单声道录制。预计这些代理将进行交互 最好是具有开放的通道。分析是以测量为基础的 的断开时间、阻塞时间、猝发周期和电压依赖关系 阻止。这项研究有望提供有关 钙拮抗剂的临床应用。

项目成果

Preferential block of skeletal muscle sodium channels by geographutoxin II, a new peptide toxin from Conus geographus.

Geographutoxin II（一种来自 Conus geographus 的新型肽毒素）优先阻断骨骼肌钠通道。

• DOI: 10.1007/bf00580684
• 发表时间: 1986
• 期刊: Pflugers Archiv : European journal of physiology
• 作者: Kobayashi,M;Wu,CH;Yoshii,M;Narahashi,T;Nakamura,H;Kobayashi,J;Ohizumi,Y
• 通讯作者: Ohizumi,Y

Amiodarone-induced block of sodium current in isolated cardiac cells.

胺碘酮诱导分离心肌细胞钠电流阻断。

• 发表时间: 1987
• 期刊: The Journal of pharmacology and experimental therapeutics
• 作者: Follmer,CH;Aomine,M;Yeh,JZ;Singer,DH
• 通讯作者: Singer,DH

Characterization of two types of calcium channels in mouse neuroblastoma cells.

小鼠神经母细胞瘤细胞中两种钙通道的表征。

• DOI: 10.1113/jphysiol.1987.sp016406
• 发表时间: 1987
• 期刊: The Journal of physiology
• 作者: Narahashi,T;Tsunoo,A;Yoshii,M
• 通讯作者: Yoshii,M

Block of calcium channels by enkephalin and somatostatin in neuroblastoma-glioma hybrid NG108-15 cells.

神经母细胞瘤-神经胶质瘤杂交 NG108-15 细胞中脑啡肽和生长抑素阻断钙通道。

• DOI: 10.1073/pnas.83.24.9832
• 发表时间: 1986
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Tsunoo,A;Yoshii,M;Narahashi,T
• 通讯作者: Narahashi,T

Maitotoxin-induced membrane current in neuroblastoma cells.

麦托毒素诱导神经母细胞瘤细胞膜电流。

• DOI: 10.1016/0006-8993(87)91200-5
• 发表时间: 1987
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Yoshii,M;Tsunoo,A;Kuroda,Y;Wu,CH;Narahashi,T
• 通讯作者: Narahashi,T