Intermittent Cold Exposure on the Endothelin System

描述（由申请人提供）：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。心血管疾病死亡率和发病率最高的季节是寒冷的冬季。低温会增加高血压患者高血压的严重程度。因此，对冷致高血压（CIH）发病机制的研究具有重要意义。我们的长期目标是了解低温作为心血管疾病的一个因素的作用，以制定预防和治疗策略。间歇性暴露于寒冷（5°C; 41°F）的大鼠在暴露三周内出现高血压，包括心脏肥厚。目前，这是唯一的“自然”形式的实验诱导高血压，不需要手术，药物，激素或基因操作。基于我们强有力的初步数据，我们的中心假设是间歇性冷暴露激活内皮素（ET）系统，并且ET的激活在CIH的发展和维持中起作用。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。本研究主要围绕以下四个方面展开：1)研究间歇性低温对内皮素-1前原和et转化酶表达及ET-1生成的影响；2)确定间歇性冷暴露对ETA、ETB1和ETB2受体表达的调控作用；3)观察慢性阻断ETA、ETB1和ETA+B受体对CIH和心脏血管肥大的影响；4)评估心脏AT1受体在冷诱导心脏ET产生增加中的作用，以及心脏矿化皮质激素受体（MR）在冷诱导心脏ETA/ETB2受体调节中的作用。由于CIH大鼠模型最初是在我们的实验室开发的，因此我们具有独特的优势来承担拟议的研究。这项工作将首次使用最先进的技术来评估ET系统在CIH（一种新型高血压模型）中的潜在作用。该结果将揭示预防的新见解，并将允许优化与感冒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，冬季有户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.