CARDIOVASCULAR EFFECTS OF COCAINE

可卡因仍然被广泛使用，尽管有越来越多的报道表明 特殊的心肌毒性。目前，我们无法确定 有患可卡因相关心脏病风险的个人。每个人都不同 在它们对毒性反应的敏感性方面，目前还没有动物模型 可卡因引起的心脏病已被描述为反映了这一点。 可变性。使用几个心血管变量的测量 (例如，心输出量、全身血管阻力、每搏量和 心率)，我们已经确定了反应特征的可变性 这与可卡因引起的心肌病的变异性有关，但 而不是升压反应。在我们的大多数研究中，我们将 将人口分为两组，以便于我们使用心脏 输出(CO)响应。可卡因注射引起了一致的 减少血管反应者(以前称为反应者)中的一氧化碳。 血管反应者发生超微结构的几率更高 心肌异常(如肌浆网扩张， 肌原纤维和线粒体异常和局灶性肌细胞溶解 在反复服用可卡因后，这些变化没有那么严重 或在没有CO减少的大鼠中缺失(混合反应者，以前 无响应者)。血管反应者的心脏增加幅度也较小 体循环血管阻力(SVR)增加更快。几个 药物独立地改变CO和动脉压的反应 这表明，不同的机制参与其中。在此应用程序中， 我们建议重点关注我们的发现的两个方面； 心血管疾病和心肌病的反应性。首先，我们将 确定CO减少和增加的具体原因 在SVR中，通过测量可能负责 可变性，如收缩能力、冠状动脉和骨骼肌血管 反应性和交感神经活动。此外，我们还将审查 副交感神经和交感神经音调的相对贡献 可卡因和可卡因后心脏分化的可能原因 对肾上腺素能药物敏感。这些研究将确定导致 CO和SVR变异性。第二，我们将执行形态测量以 大鼠心肌超微结构改变的特征 可卡因处理大鼠，并与儿茶酚胺和中枢神经系统进行比较 刺激诱发的心肌病。浅谈超微结构的成因 变化将直接使用选择性拮抗剂和心脏 神经丧失。我们的结果将表征差异的原因 对可卡因引起的心血管反应和心肌损伤的敏感性 疾病，并可能为敏感患者提供特定的治疗 可卡因引发的心脏病。此外，我们的研究提供了一种新颖的 可卡因或压力相关风险较高的个人所采用的模式 心脏病可能会被识别出来。

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.