ALCOHOL MODULATION OF CARDIAC CALCIUM CHANNELS

心脏钙通道的酒精调节

基本信息

批准号：
2851583
负责人：
DENNIS A TWOMBLY
金额：
$ 22.72万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-01 至 2004-03-31
项目状态：
已结题

项目摘要

Alcohol exerts a variety of actions on the cardiovascular system, the nervous system, and other organs. Clinical studies, have linked alcohol consumption with a number of asymptomatic and overt cardiovascular abnormalities, including cardiomyopathy, hypertension, arrhythmias, heart failure, and stroke. The mechanisms responsible for these various problems are not well understood. In the nervous system, voltage activated calcium channels and certain ligand-gated channels arc particularly sensitive targets of alcohol. These channels are suspected of being instrumental in acute intoxication and withdrawal. In cardiac tissues, calcium channels play a key role in rhythmicity, conduction, and excitation-contraction coupling. These channels are a major site of control by endogenous hormones and transmitters, and by therapeutic drugs. Calcium channels have been directly linked to a number of the actions of ethanol on the heart. Ethanol interferes with contractility in a variety of models, and it reduces electrically-stimulated calcium transients in ventricular myocytes. Our preliminary data with rat myocytes, and results from other laboratories, have confirmed that ethanol blocks L-type calcium channels in isolated cardiac cells. Defining how alcohol affects the physiology and regulation of these channels is essential in explaining immediate consequences of alcohol ingestion, as well as events that occur during prolonged periods of alcohol ethanol abuse. The overall objective of the proposed studies is to use whole-cell patch clamp techniques to analyze ethanol modulation of cardiac calcium channels. Ventricular myocytes will be dissociated from cardiac tissues of adult rats, and subjected to acute alcohol exposure. Biophysical and pharmacological experiments will evaluate calcium channel function under these conditions, and impossible mechanisms of channel modulation. Certain second messenger systems are known to exert regulatory control over calcium channel function in heart cells. Among these, the beta- adrenergic/cAMP/PKA pathway is a critical mechanism for enhancing L-type calcium channels and stimulating cardiac contractility. We will therefore test the hypothesis that ethanol alters regulation of channels through this signal transduction system. Our preliminary data have shown that ethanol not only blocks currents stimulated via the beta-adrenergic system, but it also inhibits desensitization of the coupling process. We have also just completed exciting new preliminary studies demonstrating that ethanol is capable of reversing or occluding nifedipine-induced channel block. This novel action may have major implications, given the widespread clinical use of dihydropyridines and other calcium channel antagonists. Drug interactions of this type will be an important focus of the project.

酒精在心血管系统上采取多种作用，神经系统和其他器官。临床研究，已经连接了酒精多种无症状和明显的心血管消费异常，包括心肌病，高血压，心律不齐，心力衰竭和中风。负责这些各种的机制问题不太了解。在神经系统中，电压激活的钙通道和某些配体门控通道弧尤其是酒精的敏感靶标。怀疑这些渠道在急性中毒和戒断中发挥了作用。在心脏组织，钙通道在节奏性，传导中起关键作用和激发反应耦合。这些渠道是主要网站通过内源激素和发射器控制的控制，以及通过治疗毒品。钙通道已直接链接到许多乙醇对心脏的作用。乙醇干扰收缩性在多种型号中，它可以减少电刺激的钙室心肌细胞的瞬态。我们的初步数据与老鼠心肌细胞和其他实验室的结果已经确认乙醇阻断分离的心脏细胞中的L型钙通道。定义酒精如何影响它们的生理和调节渠道对于解释酒精的直接后果至关重要摄入，以及在长时间期间发生的事件滥用酒精乙醇。拟议研究的总体目标是使用全细胞斑块夹技术分析乙醇心脏钙通道的调节。心室心肌细胞将与成年大鼠的心脏组织解离，并急性酒精暴露。生物物理和药理学实验将在这些条件下评估钙通道功能，而不可能通道调制的机制。某些第二会系统是已知可以对心脏中钙通道功能发挥调节性控制细胞。其中，β-肾上腺素能/cAMP/PKA途径是关键增强L型钙通道和刺激心脏的机制收缩力。因此，我们将检验乙醇改变的假设通过此信号转导系统调节通道。我们的初步数据表明，乙醇不仅可以阻止电流通过β-肾上腺素系统刺激，但也抑制耦合过程的脱敏。我们也刚刚完成令人兴奋的新初步研究表明乙醇有能力逆转或阻断硝苯地平诱导的通道块。这本小说鉴于广泛的临床用途，行动可能具有重大影响二氢吡啶和其他钙通道拮抗剂。药品这种类型的互动将是该项目的重要重点。