CARDIOVASCULAR EFFECTS OF COCAINE

可卡因对心血管的影响

• 批准号: 2377359
• 负责人: MARK M KNUEPFER
• 金额: $ 15.11万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-03-01 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2377359
• 关键词: baroreflex; cardiac output; cardiovascular function; cocaine; denervation; disease /disorder proneness /risk; electrocardiography; heart innervation; histopathology; laboratory rat; myocardium disorder; myofibrils; sarcoplasmic reticulum; toxicology; vascular resistance

Cocaine is still widely used despite increasing reports of apparent idiosyncratic myocardial toxicity. At present, we are unable to identify individuals at risk for cocaine-related cardiac disease. Individuals vary in their susceptibility to toxic responses yet no animal model for cocaine-induced cardiac disease had been described reflecting this variability. Using measurements of several cardiovascular variables (e.g. cardiac output, systemic vascular resistance, stroke volume, and heart rate), we have identified variability in response characteristics that is related to variability in cocaine-induced cardiomyopathies but not to pressor responses. In most of our studies, we have separated the population into two groups to facilitate our analysis using cardiac output (CO) responses. Cocaine administration elicits consistent decreases in CO in vascular responders (formerly named responders). Vascular responders have a greater incidence of ultrastructural myocardial abnormalities (eg., dilated sarcoplasmic reticulum, myofibrillar and mitochondrial abnormalities and focal myocytolysis) after repeated cocaine administration while these changes are less severe or absent in rats without a decrease in CO (mixed responders, formerly nonresponders). Vascular responders also have smaller increases in heart rate and greater increases in systemic vascular resistance (SVR). Several agents alter the CO and arterial pressure responses independently suggesting that different mechanisms are involved. In this application, we propose to focus on two aspects of our findings; the variability in cardiovascular and in cardiomyopathic responsiveness. First, we will determine the specific cause of the decrease in CO and enhanced increase in SVR by measuring specific parameters that could be responsible for the variability such as contractility, coronary and skeletal muscle vascular responsivity and sympathetic nerve activity. In addition, we will examine the relative contribution of parasympathetic and sympathetic tone before and after cocaine and the possible causes of differential cardiac sensitivity to adrenergic agents. These studies will define causes of the CO and SVR variability. Second, we will perform morphometry to characterize the ultrastructural alterations in the myocardium of cocaine-treated rats and compare these to catecholamine and CNS stimulation-induced cardiomyopathies. The causes of ultrastructural changes will be examined directly using selective antagonists and cardiac denervation. Our results will characterize the causes of differential sensitivity to cocaine-induced cardiovascular responses and myocardial disease and may provide specific treatments for patients sensitive to cocaine-induced cardiac disease. Furthermore, our studies offer a novel model by which individuals at greater risk for cocaine- or stress-related heart disease may be identified.

尽管有明显的报道，但可卡因仍被广泛使用 特质性心肌毒性。目前，我们无法识别 患有可卡因相关心脏病风险的人。个人有所不同 为了对有毒反应的敏感性，但没有动物模型 可卡因引起的心脏病已被描述为反映这一点 可变性。 使用几个心血管变量的测量 （例如心输出，全身血管抗性，中风量和 心率），我们已经确定了响应特征的变异性 这与可卡因诱导的心肌病的变异性有关，但 不施加响应。在我们的大多数研究中，我们分开了 人口分为两组，以促进我们的分析 输出（CO）响应。 可卡因给药会引起一致 血管反应者（以前命名为响应者）的CO下降。 血管反应者的超微结构发生率更大 心肌异常（例如，扩张的肌质网， 肌原纤维和线粒体异常和局灶性肌细胞解析） 在重复可卡因给药后，这些变化不那么严重 或大鼠没有CO降低的大鼠（混合响应者，以前 非响应者）。血管反应者的心脏增加也较小 系统性血管抗性（SVR）的速率和更大的增加。一些 代理独立改变CO和动脉压反应 表明涉及不同的机制。在此应用程序中 我们建议专注于我们发现的两个方面。变异性 心血管和心肌病的反应性。 首先，我们会的 确定CO减少并增加增加的特定原因 在SVR中，通过测量可能负责的特定参数 诸如收缩力，冠状动脉和骨骼肌血管等变异性 反应性和交感神经活动。此外，我们将检查 副交感神经和同情语气的相对贡献 在可卡因和差异心脏的可能原因之后 对肾上腺素能剂的敏感性。这些研究将定义 CO和SVR变异性。 其次，我们将执行形态计量学 表征心肌的超微结构改变 可卡因处理的大鼠，并将其与儿茶酚胺和CNS进行比较 刺激引起的心肌病。超微结构的原因 更改将使用选择性拮抗剂和心脏直接检查 神经。 我们的结果将表征差异的原因 对可卡因诱导的心血管反应和心肌的敏感性 疾病，可能为患者敏感的患者提供特定的治疗 可卡因诱导的心脏病。此外，我们的研究提供了小说 模型，与可卡因或应力有关的个人面临更大的风险 可以确定心脏病。