Intermittent Cold Exposure on the Endothelin System

在寒冷地区生活和工作的人高血压和相关疾病的患病率增加 心血管疾病(如中风和心肌梗塞)。最大的死亡率和发病率 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，关于黄斑狼疮发病机制的研究 寒性高血压(CIH)是一个强烈的指征。我们的长期目标是理解 将寒冷温度作为心血管疾病的一个因素来开发预防和治疗 战略。间歇性暴露于寒冷(5摄氏度；41华氏度)的大鼠会出现高血压，包括心脏 肥大，暴露后三周内。目前，这是唯一的“自然”形式 实验诱导的高血压，不需要手术、药物、激素或基因操作。 我们的中心假设是，基于我们强大的初步数据，间歇性寒冷暴露 激活内皮素(ET)系统，并且ET的激活在发育和 CIH的维护。这项建议的目的是确定间歇性寒冷的影响 暴露在ET系统上，并评估其对CIH的潜在贡献。拟议的研究是 以四个具体目标为中心：1)确定间歇性接触寒冷对健康的影响 内皮素前-1和内皮素转换酶的表达及内皮素-1的产生 1)；2)确定间歇性冷暴露对ETA、ETBI和ETB2调节的影响 受体表达；3)确定慢性阻断ETA、ETBI和ETA+B受体的作用 4)探讨心肌ATI受体在心肌肥厚中的作用。 冷诱导的心脏ET生成增加及心脏盐皮质激素受体的作用 (MR)在冷诱导的心脏ETA/ETB2受体调节中的作用。我们具有得天独厚的优势 进行拟议的研究，因为CIH/RAT模型最初是在我们的 实验室。拟议中的工作将首次使用最先进的技术来评估， ET系统在新型高血压模型--脑出血中的潜在作用结果将揭示新的 对预防的洞察，并将使感冒相关治疗方法得到优化 心血管疾病，这对生活在寒冷地区的人很重要，对患有 冬季外出工作，以及在人工寒冷环境中日常工作的人。

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.