GENDER EFFECTS ON THE CARDIAC TOXICITY OF ETHANOL

性别对乙醇心脏毒性的影响

• 批准号: 2803691
• 负责人: Richard H Kennedy
• 金额: $ 16.17万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2803691
• 关键词: alcoholic beverage consumption; blood chemistry; blood pressure; body weight; cardiotoxin; cardiovascular function; disease /disorder model; electrocardiography; estradiol; ethanol; gender difference; heart contraction; heart rate; hormone regulation /control mechanism; hormone therapy; hypertension; laboratory rat; male castration; myocardium disorder; sex hormones; telemetry; testosterone; vascular resistance

Clinical studies examining the influence of gender on the cardiotoxic effects of chronic ethanol intake are inconclusive with some showing that females are more sensitive to the cardiotoxicity, but others suggesting that men are more sensitive. Unfortunately, corresponding data from animal models, which provide more controlled experimental conditions, are not readily available. Experiments in the proposed project will use a rat model to test the hypotheses that: 1) males respond to chronic ethanol consumption with a more pronounced hypertension that leads to a marked cardiomyopathy; and (2) that this gender-related disparity is mediated, at least in part, by sex hormones and their response to ethanol consumption. Proposed experiments will address the following specific questions: 1) Does gender influence the effects of chronic ethanol intake on measured cardiovascular parameters? 2) Does ethanol intake affect circulating levels of sex hormones? 3) Are gender-related differences observed in castrated animals, and are the effects of castration reversed by hormone-replacement? 4) Are gender-related differences in the cardiomyopathy prevented by maintaining after-load at pre-ethanol levels? Ethanol-preferring male and female P-rats will be allowed free access to either water or an ethanol/water mixture for 16 weeks. Some animals will be castrated, and half of the castrated rats will be treated with sustained-release estradiol (females) or testosterone (males) pellets. In vivo studies examining effects of chronic ethanol intake on blood pressure and heart rate will utilize biotelemetry techniques, while cardiac contractility and vascular responsiveness will be monitored in vitro in tissues isolated after the 16 weeks. Ethanol consumption and body weight will be monitored, and blood ethanol, estradiol levels will be examined. Future experiments will use the established model to examine the cellular and molecular mechanisms underlying observed gender-associated variations. Studies could address possible differences in the effects of ethanol on hormone regulation, blood pressure regulation and/or cardiac function. Gene control, protein expression and cellular function could be examined at any of these sites.

性别对心脏毒性影响的临床研究 长期酒精摄入的影响是不确定的， 女性对心脏毒性更敏感，但其他人 这表明男人更敏感不幸的是， 来自动物模型的数据，这提供了更多的对照实验数据。 条件，并不容易获得。实验在拟议的 该项目将使用大鼠模型来测试以下假设：1）雄性 对慢性乙醇消耗的反应更明显， 高血压导致明显的心肌病;（2）这 与性别有关的差异至少部分是由性激素介导的 以及他们对乙醇消费的反应。拟议的实验将 处理以下具体问题： 1)性别是否会影响慢性乙醇摄入对 测量心血管参数？ 2)酒精摄入会影响性激素的循环水平吗？ 3)是否在去势动物中观察到性别相关差异， 阉割的效果被替代性阉割逆转了吗 4)心肌病中的性别差异是否可以通过 将后负荷维持在乙醇前的水平 将允许偏好乙醇的雄性和雌性P-大鼠自由进入 水或乙醇/水混合物中的任一种持续16周。有些动物会 被阉割，一半被阉割的大鼠将被处理， 缓释雌二醇（雌性）或睾酮（雄性）丸。 检查慢性乙醇摄入对血液影响的体内研究 血压和心率将利用生物遥测技术， 将监测心脏收缩力和血管反应性， 在16周后分离的组织中进行体外培养。乙醇消耗量和 将监测体重，血液乙醇、雌二醇水平将 接受检查。 未来的实验将使用已建立的模型来检查 观察到的与性别有关的 变化.研究可以解决以下方面可能存在的差异： 乙醇对激素调节、血压调节和/或心脏 功能基因控制、蛋白质表达和细胞功能可以 在这些网站中的任何一个进行检查。