Intermittent Cold Exposure on the Endothelin System

描述（申请人提供）：在寒冷地区生活和工作的人，高血压和相关心血管疾病（如中风和心肌梗死）的患病率增加。心血管疾病的最高死亡率和发病率发生在寒冷的冬季。寒冷的气温会增加高血压患者高血压的严重程度。因此，研究冷诱发高血压（CIH）的发病机制具有重要意义。我们的长期目标是了解寒冷温度作为心血管疾病因素的作用，以制定预防和治疗策略。大鼠间歇性暴露于寒冷（5 ℃; 41 ℉），在暴露后三周内会出现高血压，包括心脏肥大。目前，这是唯一的“自然”形式的实验性高血压，不需要手术，药物，激素或基因操作。我们的中心假设，基于我们强有力的初步数据，是间歇性冷暴露激活内皮素（ET）系统，ET激活在CIH的发展和维持中发挥作用。本提案的目的是确定间歇性冷暴露对ET系统的影响，并评估其对CIH的潜在贡献。本研究的主要目的是：1）观察间歇性冷暴露对内皮素-1（ET-1）前原和ET-转换酶表达及内皮素-1（ET-1）生成的影响; 2）观察间歇性冷暴露对内皮素受体（ETA）、内皮素受体（ETB_1）和内皮素受体（ETB_2）表达的调节作用; 3）观察慢性阻断ETA、ETB_1和ETA+B受体对CIH和心血管肥大的影响; 4）研究心脏AT 1受体在冷诱导的心脏ET产生增加中的作用，以及心脏盐皮质激素受体（MR）在冷诱导的心脏ET产生增加中的作用。心脏ETA/ETB 2受体的诱导调节。我们处于独特的位置进行拟议的研究，因为CIH大鼠模型最初是在我们的实验室开发的。拟议的工作将使用最先进的技术来评估，第一次，在CIH，一种新的高血压模型的ET系统的潜在作用。研究结果将揭示预防的新见解，并将允许优化与寒冷相关的心血管疾病的治疗方法，这对于生活在寒冷地区的人，冬季在外工作的人以及每天在人工寒冷环境中工作的人来说非常重要。

DESCRIPTION (provided by applicant): People who live and work in cold areas have an increased prevalence of hypertension and related cardiovascular diseases (e.g. stroke and myocardial infarction). The greatest mortality and morbidity due to cardiovascular diseases occur in the cold winter season. Cold temperatures increase the severity of hypertension in hypertensive patients. Therefore, studies regarding the pathogenesis of cold-induced hypertension (CIH) are strongly indicated. Our long-term goal is to understand the role of cold temperatures as a factor in cardiovascular disease for developing preventive and therapeutic strategies. Rats intermittently exposed to cold (5¿C; 41 ¿F) develop hypertension, including cardiac hypertrophy, within three weeks of exposure. Presently this is the only "natural" form of experimentally-induced hypertension, requiring no surgery, drugs, hormones or genetic manipulation. Our central hypothesis, based on our strong preliminary data, is that intermittent cold exposure activates the endothelin (ET) system and that the ET activation plays a role in the development and maintenance of CIH. The objective of this proposal is to determine the effects of intermittent cold exposure on the ET system and to assess its potential contribution to CIH. The proposed research is centered on four Specific Aims: 1) To determine the effect of intermittent exposure to cold on the expression of preproendothelin-1 and ET-converting enzyme and the production of endothelin-1 (ET-1); 2) To determine the effect of intermittent cold exposure on the regulation of ETA, ETB1 and ETB2 receptor expression; 3) To determine the effect of chronic blockade of ETA, ETB1 and ETA+B receptors on CIH and cardiac and vascular hypertrophy; 4) To evaluate the role of cardiac AT1 receptors in the cold-induced increase in cardiac ET production and the role of cardiac mineralocorticoid receptor (MR) in the cold-induced regulation of cardiac ETA/ETB2 receptors. We are uniquely positioned to undertake the proposed research because the CIH rat model was originally developed in our laboratory. The proposed work will use the state-of-the-art techniques to evaluate, for the first time, the potential role of the ET system in CIH, a novel model of hypertension. The results will reveal new insights into prevention and will allow optimization of therapeutic approaches for cold-related cardiovascular diseases, which is important for people who live in cold areas, for people who have outside duties in winter, and for people who work daily in artificial cold environment.