CARDIOVASCULAR EFFECTS OF COCAINE

尽管越来越多的报告表明， 特异质心肌毒性。目前，我们无法确定 有可卡因相关心脏病风险的人。个体差异 对毒性反应的敏感性，但没有动物模型 可卡因引起的心脏病的描述反映了这一点 可变性 使用几个心血管变量的测量 (e.g.心输出量、全身血管阻力、每搏输出量，以及 心率），我们已经确定了反应特征的变异性 这与可卡因引起的心肌病的变异性有关， 而不是加压反应。在我们的大多数研究中， 人口分为两组，以方便我们的分析，使用心脏 输出（CO）响应。 可卡因给药引起一致的 血管反应者（以前称为反应者）中的CO减少。 血管反应者有更大的发生率， 心肌异常（例如，扩张的肌浆网， 肌原纤维和线粒体异常以及局灶性肌细胞溶解） 虽然这些变化不太严重， 或在大鼠中不存在，而没有CO减少（混合反应者，以前称为 无应答者）。血管反应者也有较小的增加， 全身血管阻力（SVR）增加。几 药物独立地改变CO和动脉压反应 这表明涉及不同的机制。在本申请中， 我们建议把重点放在我们的研究结果的两个方面; 心血管和心肌病反应性。 一是 确定CO减少和增强增加的具体原因 在SVR中，通过测量可能导致 收缩性、冠状动脉和骨骼肌血管 反应性和交感神经活动。此外，我们将研究 副交感神经和交感神经紧张相对贡献之前 可卡因和可能的原因后， 对肾上腺素能药物敏感。这些研究将确定 CO和SVR变异性。 其次，我们将进行形态测量， 描述心肌超微结构的变化， 可卡因治疗的大鼠，并将其与儿茶酚胺和CNS进行比较 刺激诱发的心肌病超微结构的原因 将直接使用选择性拮抗剂和心脏 去神经 我们的研究结果将描述差异的原因 对可卡因引起的心血管反应和心肌 疾病，并可能为敏感的患者提供特定的治疗方法， 可卡因引起的心脏病此外，我们的研究提供了一个新的 根据该模型，个人患可卡因或压力相关疾病的风险更大 心脏病是可以确诊的。

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.