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.

酒精对心血管系统有多种作用，神经系统和其他器官。临床研究表明酒精与与一些无症状和明显的心血管疾病有关的消耗异常，包括心肌病、高血压、心律失常、心力衰竭和中风。负责这些不同的机制问题没有得到很好的理解。在神经系统中，电压激活的钙通道和某些配体门控通道酒精特别敏感的目标。这些渠道被怀疑有助于急性中毒和戒断。在心脏方面组织中，钙通道在节律、传导、和兴奋-收缩耦合。这些渠道是主要网站内源性激素和递质以及治疗性的控制药物。钙通道与许多乙醇对心脏的作用。乙醇干扰收缩力在各种模型中，它减少了电刺激钙心室肌细胞的瞬变。我们与大鼠的初步数据肌细胞和其他实验室的结果已经证实乙醇可阻断离体心肌细胞中的 L 型钙通道。定义酒精如何影响这些生理学和调节渠道对于解释酒精的直接后果至关重要摄入以及长时间内发生的事件酒精乙醇滥用。拟议研究的总体目标是利用全细胞膜片钳技术来分析乙醇心脏钙通道的调节。心室肌细胞将从成年大鼠的心脏组织中分离出来，并进行急性处理酒精暴露。生物物理和药理实验将在这些条件下评估钙通道功能，并且不可能信道调制机制。某些第二信使系统是已知对心脏钙通道功能进行调节控制细胞。其中，β-肾上腺素能/cAMP/PKA途径是一个关键的途径。增强L型钙通道并刺激心脏的机制收缩性。因此，我们将检验乙醇改变的假设通过该信号转导系统调节通道。我们的初步数据表明，乙醇不仅能阻断电流通过β-肾上腺素能系统刺激，但它也抑制耦合过程脱敏。我们也刚刚完成令人兴奋的新初步研究表明乙醇能够逆转或闭塞硝苯地平引起的通道阻滞。这部小说鉴于广泛的临床应用，行动可能会产生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一个重要焦点。