CARDIORESPIRATORY EFFECTS OF COCAINE

可卡因对心肺的影响

• 批准号: 3211631
• 负责人: Richard Alan Gillis
• 金额: $ 13.76万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-30 至 1990-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3211631
• 关键词: alpha adrenergic receptor; arrhythmic agent; blood pressure; cardiac output; cardiotoxin; cats; central nervous system stimulants; cocaine; coronary occlusion /thrombosis; drug abuse; drug adverse effect; heart circulation; heart contraction; heart metabolism; heart rate; heart rhythm; laboratory mouse; norepinephrine; respiratory airway volume; respiratory toxin; sudden cardiac death; swine; sympathetic nervous system; vasospasm

The aims of our proposed research are to determine: 1) the spectrum of cardiorespiratory effects that occur with cocaine administration, 2) the effect of cocaine on cardiovascular changes induced by neurally released and injected catecholamines, 3) whether cocaine augments ventricular irritability and increases susceptibility to sudden death, 4) mechanisms whereby cocaine produces changes in cardiorespiratory function, and 5) the most effective drug(s) for counteracting cocaine-induced cardiorespiratory toxicity. For this purpose cocaine will be administered i.v. to chloralose-anesthetized cats in doses ranging from 0.125 to 8 mg/kg while monitoring arterial pressure, tracheal air flow and tidal volume, heart rate, cardiac rhythm, cardiac output, myocardial contractility, myocardial lactate production, and flows from 3 vascular beds (coronary, renal and mesenteric). Cocaine will also be administered in a cat model of sympathetic mediated coronary constriction and in isolated coronary vessels of pigs. In later studies we will test cocaine in an animal model of coronary spasm. Cocaine will be evaluated on cardiovascular responses elicited by neurally-released and injected catecholamines. The role of presynaptic alpha2- adrenoceptors in modifying all of the above responses produced by cocaine will be examined by repeating experiments in animals pretreated with the alpha 2-adrenoceptor blocker, yohimbine. Cat models of ventricular irritability (coronary occlusion and reperfusion-induced changes in cardiac electrical activity, and imbalanced sympathetic cardiac drive) will be used to evaluate arrhythmogenic properties of cocaine. Mouse models of cardiac sudden death will be employed to determine whether cocaine affects coronary thrombosis. We will use sympathetic nerve recordings, intracerebroventricular injections of cocaine and specific drugs to manipulate the function of brain neurotransmitters for the purpose of elucidating the mechanisms whereby cocaine influences cardiorespiratory function. The information gained will be used as a basis for designing studies to assess which drug(s) is/are best able to counteract cocaine- induced cardiorespiratory toxicity. These studies should: 1) define dose-related cardiorespiratory effects of cocaine, 2) elucidate mechanisms whereby cocaine produces cardiorespiratory effects and 3) provide a foundation for developing drug treatments to both prevent and treat cocaine-induced cardiorespiratory toxicity.

本研究的目的是确定：1） 可卡因引起的心肺效应谱 给药，2）可卡因对心血管变化的影响 由神经释放和注射的儿茶酚胺诱导，3） 可卡因是否会增加心室的兴奋性， 对猝死的易感性，4）可卡因 产生心肺功能的变化，5）最 用于对抗可卡因诱导的 心肺毒性 为此，可卡因将 给氯醛糖麻醉的猫静脉注射，剂量范围为 从0.125至8 mg/kg，同时监测动脉压， 气管气流和潮气量，心率，心律， 心输出量，心肌收缩力，心肌乳酸 生产，并从3个血管床（冠状动脉，肾脏和 肠系膜）。 还将在以下猫模型中施用考马斯亮蓝： 交感神经介导的冠状动脉收缩， 猪的冠状动脉。 在以后的研究中，我们将测试可卡因， 冠状动脉痉挛的动物模型。 将在以下时间评价COST 由神经释放和 注射了儿茶酚胺 突触前α 2- 肾上腺素受体在修改所有上述反应产生的 可卡因将通过在动物身上重复实验来检验 用α 2肾上腺素受体阻滞剂育亨宾预处理。 心室应激性猫模型（冠状动脉闭塞和 再灌注诱导的心脏电活动变化，以及 不平衡交感心驱动）将用于评估 可卡因的致癌特性。 小鼠心脏模型 突然死亡将被用来确定可卡因是否 影响冠状动脉血栓形成 我们会用交感神经 记录，脑室内注射可卡因， 操纵大脑功能的特效药 神经递质的目的，阐明机制 由此可卡因影响心肺功能。 的 获得的信息将用作设计研究的基础， 评估哪种药物最能对抗可卡因- 引起心肺毒性。 这些研究应该：1）定义 可卡因的剂量相关心肺效应，2）阐明 可卡因产生心肺效应的机制 和3）为开发药物治疗提供基础， 预防和治疗可卡因引起的心肺毒性。