CA++ BLOCKERS IN ISCHEMIC/THROMBOTIC SUDDEN DEATH

用于心脏病的钙通道阻滞剂硝苯地平已被发现 以临床剂量预防严重的实验性血栓形成 挑战。尽管钙离子阻滞剂是公认的血管扩张剂， 抗痉挛和抗心律失常，越来越多的证据表明 抗血栓作用可能与其临床疗效有关。它是 因此建议以系统的量化方式来测试， 这类药物在多大程度上是抗血栓的，并将防止 血栓性猝死。这将在一只特征良好的小鼠身上完成 既便宜又量化的猝死模型。射程 挑战代理的数量将大幅扩大，以提供广泛的 种类繁多，从静脉凝血酶，花生四烯酸， 胶原、ADP和血栓素A2激动剂对血小板活化因子的作用 (PAF-ACETER)。PAF-乙醚致猝死为过敏性死亡 而不是血栓形成，因为小鼠血小板对PAF-乙醚不敏感 聚合术语。拟评价的钙离子阻断药物有 硝苯地平、维拉帕米、地尔硫卓、培己苯和尼群地平。这些钙离子 阻断药物也将被比作钙调素拮抗剂。 三氟拉嗪、吡莫齐特和喷氟利多。我们将做出特别的努力 评估激发后和治疗前的疗效。 组织病理学分析将被用来将血栓形成与 保护。心电地形图将被用来评估 抗心律失常作用与其保护作用有关。 长期目标是为一种 钙离子相关药物的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.