CELLULAR MECHANISMS OF CRACK COCAINES CARDIAC TOXICITY

描述：申请者摘要 据报道，可卡因和强效可卡因的滥用在临床上会产生 严重的心脏抑制，在某些患者中可能表现为急性 心力衰竭伴心源性肺水肿。最近在我们的研究中 实验室表明，可卡因的负性肌力作用是 部分通过毒鼠碱对心肌细胞的刺激而介导，并可能 在没有局部麻醉效果的低剂量下发生；甲基埃戈尼定(Meg， 可卡因吸食的主要热解产物)效力更强 而不是可卡因作为心肌上的毒碱激动剂。会议的主要目标是 建议的实验是为了描绘细胞和分子机制。 受可卡因和脑磁图刺激的心肌毒碱的影响 受体，评估它们在收缩方面的功能意义 性能，并确定防止或扭转其急性和 亚急性心肌抑制作用的体内研究。各种分子和 将使用细胞技术来识别类型(S)和亚型(S) 可卡因对M受体的影响与脑磁图的对比 数据表明可能不同，并描绘了特定的蜂窝位置 行动。我们的发现的生理意义将在一个 我们预测的缺血模型将证明这些潜在的 加重缺血后心功能不全或晕厥的药物。 实验将在雪貂心肌和转基因细胞上进行 线条；然而，我们将通过确证的方式来证明它们与人类的相关性 人类心肌细胞的实验。总而言之，这些研究应该 加深我们对细胞机制和功能的理解 可卡因和脑磁图与心肌毒副反应相互作用的意义 受体，并确定潜在的心脏治疗方法 滥用这些物质可能发生的抑郁症，即使在患者中也是如此 拥有正常的心脏。

DESCRIPTION: Applicant's Abstract Cocaine and crack cocaine abuse have been reported to produce clinically significant cardiac depression, which in some patients may present as acute heart failure with cardiogenic pulmonary edema. Recent studies in our laboratory indicate that the negative inotropic actions of cocaine are mediated in part by muscarinic stimulation of the cardiac myocyte and may occur at low doses devoid of local anesthetic effect; methylecgonidine (MEG, the principle pyrolysis product of crack cocaine smoking) is more potent than cocaine as a muscarinic agonist on myocardium. The major goals of the proposed experiments are to delineate the cellular and molecular mechanisms that are affected by cocaine and MEG stimulation of cardiac muscarinic receptors, evaluate their functional significance with regard to contractile performance, and identify approaches to prevent or reverse their acute and subacute myocardial depressant effect in vivo. A variety of molecular and cellular techniques will be employed to identify the type(s) and subtype(s) of muscarinic receptors affected by cocaine versus MEG, which physiologic data indicate may differ, and to delineate specific cellular sites of action. The physiological significance of our findings will be tested in a model of ischemia that we predict will demonstrate the potential for these agents to exacerbate post ischemic cardiac dysfunction, or stunning. Experiments will be performed with ferret myocardium and transfected cell lines; however, we will demonstrate their relevance to man by confirmatory experiments with human myocytes. Taken together, these studies should enhance our understanding of the cellular mechanisms and functional significance of cocaine and MEG interaction with the cardiac muscarinic receptors and identify potential therapeutic approaches to the cardiac depression that can occur with abuse of these substances, even in patients with normal hearts.