CONTROL OF STRESS RESPONSE IN RATS BY ENERGY SUBSTRATES

能量基质对大鼠应激反应的控制

基本信息

批准号：
3241932
负责人：
ERIC P. WIDMAIER
金额：
$ 10.93万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-09-01 至 1994-08-31
项目状态：
已结题

项目摘要

The ability of an organism to respond lo challenges to its physiological homeostasis by increasing the activity of the brain- pituitary-adrenocortical hormonal axis is critical to survival in all mammals, including rats and man. In the absence of a functional adrenal cortex such challenges, or "stresses," are usually fatal. One of the most potent and reliable stimuli to secretion of adrenocorticotropic hormone (ACTH) from the pituitary is hypoglycemia, lypically induced experimentally by injections of insulin. The effect of hypoglycemia is now known to be mediated at least in part via glucose sensors in the hypothelomas. resulting in secretion of corticotropin-releasing factor (CRF) into the hypophysial-portal circulating. Conversely, in isolated rat hypothalami, hyperglycemia inhibits secretion of CRF and also of oxytocin, another hypothalamic peptide known to stimulate ACTH secretion. Failure to adequately regulate circulating products of metabolism (glucose, fatty acids) within normal limits is one of the most widespread endocrine associated disorders in human beings, and can result from numerous pathologies (diabetes, fasting). This 'rises the question of the capacity of individuals to respond to different physiological stresses, such as hemorrhage, during periods of abnormal metabolic status (hyperglycemia, hyperlipidemia). Fatty acids have been shown lo inhibit secretion of growth hormone in rats and man, at both the hypothalamic and pilutuary level. Since one of the major functions of adrenal glucoconlcoids is to catabolize triglycerides in order to provide usable energy substrates for the brain, it may well be that fatty acids, like glucose, inhibit the secretion of CRF and AGTH. Therefore, the long term goals of these projects will be to characterize in detail the effects of glucose and fatty acids on secretion of CRF and ACTH at the tissue or cellular level, and to relate these effects to the ability of rats to respond to stress in vivo under periods of experimentally altered intermediary metabolism. The role of other substances that themselves influence intermediary metabolism, such as catecholamines, in activating CRF release will also be examined. These studies will also determine the ontogeny of the ACTH and corticosterone secretory responses to insulin-induced hypoglycemia, since young rats typically show reduced sensitivity to certain stimuli that produce robust secretory responses in adults. Similarly, human newborns also undergo a period of abnormal responsivity to some, but not all, types of stress. Finally, the effects of hyperglycemia on suckling-induced secretion of oxytocin in rats will be examined, since glucose decreases oxytocin secretion in vitro, and since a relatively high proportion of pregnant women develop gestational deabetes in the last trimester of pregnancy, resulting in chronic hyperglycemia.

有机体应对其挑战的能力通过增加大脑的活性来生理稳态垂体 - 肾上腺皮质激素轴对生存至关重要所有哺乳动物，包括老鼠和人。在没有功能性肾上腺皮质此类挑战或“压力”是通常致命。最有效，最可靠的刺激之一垂体中肾上腺皮质激素（ACTH）的分泌是低血糖，通过注射液化性诱导的胰岛素。现在已知低血糖的作用是介导的至少部分通过下皮瘤中的葡萄糖传感器。导致皮质激素释放因子（CRF）分泌到垂体循环。相反，在孤立的大鼠中下丘脑，高血糖抑制CRF的分泌以及催产素，另一种已知刺激ACTH的下丘脑肽分泌。无法充分调节在正常极限内代谢（葡萄糖，脂肪酸）是人类中最广泛的内分泌相关疾病，并且可以由许多病理（糖尿病，禁食）产生。这 '提出了个人回应能力的问题不同的生理压力，例如出血异常代谢状态（高血糖，高脂血症）。脂肪酸已显示出LO抑制分泌大鼠和人的生长激素，下丘脑和进出级。由于肾上腺的主要功能之一葡萄糖聚合物是为了分解甘油三酸酯，以提供大脑的可用能量基板很可能是脂肪酸，例如葡萄糖，抑制CRF和AGTH的分泌。因此，这些项目的长期目标将是详细描述葡萄糖和脂肪酸对在组织或细胞水平上分泌CRF和ACTH，并分泌将这些影响与大鼠应对压力的能力联系起来体内实验改变的时期代谢。自己影响的其他物质的作用激活CRF的中介代谢，例如儿茶酚胺也将检查发布。这些研究还将确定 ACTH和皮质酮分泌反应的个体发育胰岛素诱导的低血糖，因为年轻大鼠通常显示对某些产生强大的刺激的敏感性降低成人的分泌反应。同样，人类新生儿也对某些但不是全部的反应性异常，压力类型。最后，高血糖对将检查哺乳引起的大鼠催产素的分泌，由于葡萄糖会在体外降低催产素的分泌，因此孕妇的比例相对较高在怀孕的最后三个月中的剪断，导致慢性高血糖。