Intermittent Cold Exposure on the Endothelin System

在寒冷地区生活和工作的人高血压及相关疾病的患病率增加。 心血管疾病（如中风和心肌梗塞）。最高的死亡率和发病率 由于心血管疾病发生在寒冷的冬季。寒冷的气温增加了 高血压患者的高血压严重程度。因此，关于发病机制的研究 冷诱发的高血压（CIH）有强烈的适应症。我们的长期目标是了解 寒冷温度作为心血管疾病的一个因素， 战略布局大鼠间歇性暴露于寒冷（5 ℃; 41 ℉）会产生高血压，包括心脏病。 暴露后三周内出现肥大目前，这是唯一的“自然”形式。 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，是间歇性的寒冷暴露， 激活内皮素（ET）系统，ET激活在发育中起作用， CIH的维护。这项建议的目的是确定间歇性寒冷的影响， 暴露于ET系统，并评估其对CIH的潜在贡献。拟议的研究是 主要有四个具体目标：1）确定间歇性暴露于寒冷对 前内皮素原-1和内皮素转换酶的表达及内皮素-1（ET-1）的产生 1）; 2）确定间歇性冷暴露对ETA、ETBi和ETB2的调节作用 3）观察长期阻断ETA、ETBi和ETA + B受体的作用 4）研究心脏ATi受体在CIH和心血管肥大中的作用， 冷诱导的心脏ET产生增加和心脏盐皮质激素受体的作用 (MR)心脏ETA/ETB2受体的冷诱导调节。我们有独特的优势， 进行拟议的研究，因为CIH/大鼠模型最初是在我们的 实验室拟议的工作将使用最先进的技术来评估，第一次， ET系统在CIH（一种新的高血压模型）中的潜在作用。结果将揭示新的 深入了解预防，并将允许优化治疗方法，为感冒相关的 心血管疾病，这对生活在寒冷地区的人很重要， 冬季户外工作，以及在人工寒冷环境中日常工作的人员。

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, ETBi and ETB2 receptor expression; 3) To determine the effect of chronic blockade of ETA, ETBi and ETA+B receptors on CIH and cardiac and vascular hypertrophy; 4) To evaluate the role of cardiac ATi 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.