MECHANISM OF CHRONIC ALCOHOL INDUCED CARDIOMYOPATHY

慢性酒精诱发心肌病的机制

• 批准号: 6094141
• 负责人: CHE-PING CHENG
• 金额: $ 32.63万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6094141
• 关键词: ACE inhibitors; G protein; adenylate cyclase; alcoholism /alcohol abuse; angiotensin II; calcium flux; cardiac myocytes; chronic disease /disorder; congestive heart failure; cyclic AMP; dogs; drug interactions; ethanol; hypertrophic myocardiopathy; irbesartan; isoproterenol; longitudinal animal study; muscle contraction; neuroendocrine system; nutrition related tag; protein kinase C; renin angiotensin system; sarcolemma; toxicology; vasodilators

This grant will investigate the mechanism of chronic alcohol- induced dilated cardiomyopathy (ADCM), by longitudinally assessing the structural and functional responses of the left ventricle (LV) and isolated cardiomyocytes to chronic alcohol intake. In addition, the role of the renin-angiotensin system (RAS) and the alterations in its intracellular signaling in producing ADCM will be determined. We will test the following specific Hypotheses: [H1] Chronic alcohol intake produces direct depressions in cardiomyocyte contraction, relaxation, [Ca2+]i transient and sarcolemmal Ca2+ channel activity (ICa,L), and thus causes [H2] a progressive impairment of LV systolic, diastolic function, and leads to congestive heart failure, and [H3] the most important factor in promoting the transition to ADCM is the alcohol-induced, sustained activation of circulating and cardiac RAS. This results in alterations in the AT1 receptor-coupled, protein kinase C and/or inhibitory G protein (Gi)-mediated responses of the LV and myocytes to angiotensin II (ANG II). Thus, [H4] blocking the RAS with chronic ACE inhibition or ANG II AT1 receptor blocker will blunt or prevent the chronic alcohol- induced functional and structural changes. The studies will be conducted in three control and four experimental groups studied over eight months: 1) uninstrumented alcohol-fed (22 percent alcohol once per day, providing 33 percent of total daily caloric intake); 2) instrumented alcohol-fed; 3) instrumented alcohol- ramipril (ACE inhibitor, 0.1 mg/kg/day)-fed; 4) instrumented alcohol-irbesartan (ANG II AT1 blocker, 5 mg/kg/day)-fed. The control groups will consist of age-matched dogs under identical conditions except dogs in the control groups will not receive alcohol. Serial changes of cardiac systolic and diastolic function and RAS activation will be quantitated in these conscious dogs, chronically instrumented to measure LV pressures and volume. Cell contractile function, [Ca2+]i transient and ICa,L will be serially measured in freshly isolated cardiomyocytes from the LV obtained by biopsy from the same animals. Myocytes will be studied under conditions with superfusion of: 1) calcium, 2) isoproterenol, 3) pimobendan, 4) alcohol, and 5) ANG II. In addition, the studies of myocytes response to ANG II will be repeated after preincubation with an AT1 receptor blocker, a protein kinase C inhibitor, or a Gi protein inhibitor, before, during and after the development of ADCM. These studies will be the first detailed longitudinal studies of cardiac and myocyte structure, function, [Ca2+]i transient, ICa,L during chronic alcohol intake. In addition, these studies will provide unique information on the role of the RAS and the mechanism of ADCM. These studies are necessary to extend our knowledge about the mechanism in the development of ADCM and help target therapy for ADCM.

该基金将通过纵向评估左心室（LV）和分离的心肌细胞对慢性酒精摄入的结构和功能反应，研究慢性酒精诱导的扩张型心肌病（ADCM）的机制。 此外，将确定肾素-血管紧张素系统（RAS）的作用及其细胞内信号传导在产生ADCM中的改变。 我们将检验以下具体假设：[H1]慢性酒精摄入会直接抑制心肌细胞收缩、舒张、[Ca 2 +]i瞬时和肌膜Ca 2+通道活性（伊卡，L），从而导致[H2] LV收缩、舒张功能的进行性损害，并导致充血性心力衰竭，[H3]促进向ADCM转变的最重要因素是酒精诱导的循环和心脏RAS的持续激活。 这导致LV和肌细胞对血管紧张素II（ANG II）的AT 1受体偶联、蛋白激酶C和/或抑制性G蛋白（Gi）介导的反应发生改变。因此，[H4]阻断RAS与慢性ACE抑制剂或ANG II AT 1受体阻滞剂将钝化或防止慢性酒精诱导的功能和结构变化。 这些研究将在三个对照组和四个实验组中进行，为期八个月：1）无仪器酒精喂养（22%酒精，每天一次，提供每日总热量摄入的33%）; 2）仪器酒精喂养; 3）仪器酒精-ramietine（ACE抑制剂，0.1 mg/kg/天）-饲喂; 4）仪器酒精-厄贝沙坦（ANG II AT 1阻滞剂，5 mg/kg/天）-饲喂。 对照组将由相同条件下年龄匹配的犬组成，但对照组中的犬不接受酒精。 将在这些清醒犬中定量心脏收缩和舒张功能以及RAS激活的连续变化，长期使用仪器测量LV压力和容量。 将在来自相同动物的通过活检获得的LV的新鲜分离的心肌细胞中连续测量细胞收缩功能、[Ca 2 +]i瞬时和伊卡，L。 将在灌流以下物质的条件下研究肌细胞：1）钙、2）异丙肾上腺素、3）匹莫苯、4）乙醇和5）ANG II。 此外，在ADCM发生之前、期间和之后，在与AT 1受体阻断剂、蛋白激酶C抑制剂或Gi蛋白抑制剂预孵育后，将重复进行肌细胞对ANG II反应的研究。 这些研究将是第一个详细的纵向研究心脏和心肌细胞的结构，功能，[Ca 2 +]i瞬态，伊卡，L在慢性酒精摄入。 此外，这些研究将提供关于RAS作用和ADCM机制的独特信息。 这些研究对于扩展我们对ADCM发生机制的认识和帮助ADCM的靶向治疗是必要的。