CARDIOVASCULAR EFFECTS OF COCAINE

可卡因是一种有效的中枢神经系统兴奋剂， 临床用途有限的麻醉剂，已成为 在美国最广泛滥用的药物，由于缺乏 根据科学数据，可卡因通常被认为是一种 “安全”的药物，副作用最小，估计在10至 2000万人滥用可卡因 研究描述了 可卡因对心血管的影响是适度的升压， 反应和心动过速可能是由于直接增强 儿茶酚胺能活性和间接（CNS介导） 交感神经兴奋 临床报告表明可卡因可能 导致人类心肌病。 此类报告的发生率 随着游离碱可卡因（“快克”）的使用越来越多， 强效可卡因 我们认为这需要详细的 确定急性和慢性可卡因影响的研究 在受控条件下给药，并确定 可卡因对血管系统发挥作用的机制 和心肌。 可卡因对血管的影响将被分析 在清醒的自由活动的大鼠中， 动脉压、心率和局部血流 肠系膜和后肢血管床。 的机制 将使用以下方法确定引起的特定心血管效应 选择性受体拮抗剂、局麻药和肾上腺切除术 在急性或慢性可卡因之后。 此外，组织中的儿茶酚胺 将在长期服用可卡因后估计周转率， 识别交感神经活动的持续变化。 的 将确定心肌病的发病率和严重程度 通过测量心输出量、心肌细胞水平 肌酸磷酸激酶和解剖学上的尸检，光和 心肌的电镜分析。 的机制 将使用以下公式推导出产生心脏缺血的原因： 血管痉挛和血栓闭塞的选择性拮抗剂。 的 可卡因对压力感受器反射功能的影响将在 非麻醉正常大鼠和去气压神经大鼠 交感神经活动和心率对可卡因的反应。 还将检查影响压力反射活性的CNS部位。 最后，“游离碱”可卡因对心血管的影响 将其功能与盐酸可卡因的功能进行比较。 的 拟议的研究是一种综合方法， 三个调查员的专业知识。 这种方法将是 有助于确定可卡因影响 血管张力，对功能和病理影响 可卡因对心肌的作用，对可卡因作为一种 中枢交感神经兴奋药，合理用药 毒性和游离碱可卡因的相对危险性。

Cocaine is a potent central nervous system stimulant and local anesthetic with limited clinical usefulness that has become one of the most widely abused drugs in the U.S. Due to the lack of sufficient scientific data, cocaine is generally considered a "safe" drug with minimal side effects amongst the estimated 10 to 20 million people who misuse cocaine. Studies describing the cardiovascular effects of cocaine have noted a modest pressor response and tachycardia presumably due to direct potentiation of catecholaminergic activity and indirect (CNS-mediated) sympathoexcitation. Clinical reports suggest that cocaine may cause cardiac myopathies in humans. The incidence of such reports is increasing as is the use of free base cocaine ("crack"), a more potent form of cocaine. We believe this necessitates detailed studies to define the effects of acute and chronic cocaine administration under controlled conditions and to determine the mechanisms by which cocaine elicits its effects on the vasculature and myocardium. The vascular effects of cocaine will be analyzed in awake, freely-moving rats instrumented for measurement of arterial pressure, heart rate and regional blood flows in the mesenteric and hindquarter vascular beds. The mechanisms by which specific cardiovascular effects are caused will be identified using selective receptor antagonists, local anesthetics and adrenalectomy after acute or chronic cocaine. Furthermore, tissue catecholamine turnover will be estimated after chronic cocaine administration to identify sustained alterations in sympathetic nerve activity. The incidence and severity of cardiomyopathies will be determined functionally by measuring cardiac output, levels of myocardial creatine phosphokinase and anatomically by postmortem, light and electron microscopic analysis of the myocardium. The mechanisms by which cardiac ischemia are produced will be deduced using selective antagonists for vasospasm and thrombotic occlusion. The effect of cocaine on baroreflex function will be determined in unanesthetized normal and baro-denervated rats by recording sympathetic nerve activity and heart rate responses to cocaine. CNS sites affecting baroreflex activity will also be examined. Finally, the effect of "free base" cocaine on cardiovascular function will be compared to that of cocaine hydrochloride. The proposed studies represent a comprehensive approach utilizing the combined expertise of three investigators. This approach will be instrumental in determining mechanisms whereby cocaine affects vascular tone, on the functional and pathological effects of cocaine on the myocardium, on the proposed role of cocaine as a centrally acting sympathoexcitatory agent, on rational drug therapy for toxicity and on the relative dangers of free base cocaine.