CA++ BLOCKERS IN ISCHEMIC/THROMBOTIC SUDDEN DEATH

硝苯地平是一种用于心脏病学的钙通道阻滞剂， 在临床剂量下保护免受严重的实验性血栓形成 挑战. 虽然Ca++阻滞剂被认为是血管舒张剂， 止痉挛和抗痉挛，证据越来越多， 抗血栓作用可能有助于其临床疗效。 是 因此，建议以系统的定量方式测试， 在一定程度上，这类药物是抗血栓形成的， 血栓性猝死 这将在一个良好表征的小鼠中完成 这是一个既便宜又定量的猝死模型。 范围 挑战代理将大大扩大，以提供广泛的 各种类别，从静脉内凝血酶，花生四烯酸， 胶原、ADP和血栓素A2血小板活化因子激动剂 （PAF-乙酸酯）。 PAF-醋酸酯引起的猝死是过敏性的， 而不是血栓形成，因为小鼠血小板对PAF-乙酰不敏感， 聚合的条件。 待评价的Ca++阻断药物为 硝苯地平、维拉帕米、地尔硫卓、哌克西林和尼群地平。 这些Ca++ 阻断药物也将与钙调素拮抗剂进行比较 三氟拉嗪、匹莫齐特和五氟利多。 将作出特别的努力 评价攻毒后和治疗前的疗效。 将使用组织学分析将血栓形成与 保护 EKG将用于评估 抗肿瘤作用有助于保护作用。 长期目标是为建立一个健全的实验基础， 是钙离子相关药物重要和有意义的新应用。

Nifedipine, a Ca++ channel blocking drug used in cardiology, has been found to protect in clinical doses against a severe experimental thrombotic challenge. Although the Ca++ blockers are recognized as vasodilatory, antispasmodic and antiarrhythmic, evidence is accumulating that the antithrombotic effect may contribute to their clinical efficacy. It is therefore proposed to test, in a systematic quantitative manner, to what extent this class of drugs is antithrombotic and will protect against thrombotic sudden death. This will be done in a well-characterized mouse sudden death model which is both inexpensive and quantitative. The range of challenge agents will be substantially expanded to provide a wide variety of classes, ranging from intravenous thrombin, arachidonic acid, collagen, ADP and thromboxane A2 agonist to platelet-activating factor (PAF-acether). Sudden death induced by PAF-acether is anaphylactic rather than thrombotic, since mouse platelets are insensitive to PAF-acether in terms of aggregation. The Ca++ blocking drugs to be evaluated are nifedipine, verapamil, diltiazem, perhexilene and nitrendipine. These Ca++ blocking drugs will also be compared to the calmodulin antagonists trifluoperazine, pimozide and penfluridol. An especial effort will be made to evaluate post-challenge as well as pretreatment efficacy. Histopathological analyses will be used to relate thrombosis to degree of protection. EKG will be used to evaluate the extent to which the antiarrhythmic effect contributes to the protective action. The long term objective is to lay a sound experimental basis for an important and significant new application for Ca++ related drugs.