CARDIOVASCULAR EFFECTS OF COCAINE

可卡因是一种强有力的中枢神经系统刺激剂和局部 临床用途有限的麻醉剂已成为 在美国滥用最广泛的药物。由于缺乏 根据足够的科学数据，可卡因通常被认为是 副作用最小的“安全”药物，估计有10到 滥用可卡因的2000万人。描述这一现象的研究 可卡因对心血管的影响已经注意到轻微的升压作用。 反应和心动过速可能是由于直接增强 儿茶酚胺能活动和间接(中枢神经系统介导) 交感神经兴奋。临床报告表明，可卡因可能会 导致人类的心脏肌病。此类报告的发生率 随着游离基可卡因(“可卡因”)的使用不断增加，一种更 强效可卡因。我们认为这需要详细的说明 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 可卡因对血管系统影响的机制 和心肌。我们将分析可卡因对血管的影响 在清醒的、自由移动的大鼠中测量 患者的动脉压、心率和局部血流量 肠系膜和后肢血管床。它们的作用机制 将使用以下方法确定引起的特定心血管影响 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，组织儿茶酚胺 营业额将在长期服用可卡因后估计为 确定交感神经活动的持续变化。这个 将确定心肌病的发生率和严重程度 通过测量心输出量，心肌细胞水平 肌酸磷酸激酶和解剖，死后，光和 心肌的电子显微镜分析。其作用机制 由此推断产生心肌缺血的原因 血管痉挛和血栓闭塞的选择性拮抗剂。这个 可卡因对压力感受器反射功能的影响将在#年确定 非麻醉正常和压力失神经大鼠的记录 交感神经活动和心率对可卡因的反应。 还将检查影响压力感受器反射活动的中枢神经系统部位。 最后，“游离碱”可卡因对心血管的影响 功能将与可卡因盐酸盐进行比较。这个 建议的研究代表了一种综合的方法，利用 三名调查人员的综合专业知识。这种方法将是 在确定可卡因影响机制方面具有重要作用 血管张力，对血管功能和病理的影响 可卡因对心肌的作用，关于可卡因作为 中枢性交感神经兴奋剂对合理药物治疗的影响 关于毒性和游离碱可卡因的相对危险。

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.