Forebrain Neurohumoral Integration in Heart Failure

描述（由申请方提供）：循环血管紧张素II（ANG II）和血浆渗透压升高可兴奋前脑终板中的神经元，包括正中核（NM或正中视前核），并增加交感神经活动（SNA）。此外，NM神经元接收来自后脑中的儿茶酚胺能细胞群的直接投射，并且在血管内容量的调节中起重要作用。低心输出量充血性心力衰竭（CHF）的临床特征是水和钠的慢性蓄积、血浆ANG II和醛固酮水平的显著增加以及SNA升高。几项研究表明，中枢或外周阻断ANG II或盐皮质激素受体和外周阻断ANG II产生导致SNA显著降低。因此，循环血管紧张素II和/或血浆钠的增加似乎作用于前脑终板神经元，以增加CHF期间SNA。本建议的总体概念是，NM神经元投射到下丘脑室旁核整合有关血浆ANG II水平，渗透压和血管内容量的信息，这种整合在CHF大鼠中改变。值得注意的是，心肺反射在CHF大鼠中减弱，并且NM的病变减弱了对血管内容量变化的几种反应。因此，CHF可能与NM神经元对心肺输入的反应性降低相关，从而有助于在存在增加的循环ANG II的情况下观察到的SNA增加。将使用细胞外记录在体内进行拟定实验，以确定单个NM神经元对外周ANG II、渗透压和心肺受体传入输入的综合反应。具体目标是：（1）确定单个NM神经元是否接受外周ANG II和渗透输入，并鉴定介导这些反应的受体，（2）确定奥斯莫-或外周ANG II-敏感NM神经元是否也接受心肺输入，以及这些上行输入是否由去甲肾上腺素能受体激活介导，（3）确定在具有已建立的CHF的大鼠中NM神经元对这些输入的基础活性和/或反应是否改变。

DESCRIPTION (provided by applicant): Elevated circulating angiotensin II (ANG II) and plasma osmolality excite neurons in the forebrain lamina terminalis including the nucleus medianus (NM or median preoptic nucleus) and increase sympathetic nerve activity (SNA). Additionally, NM neurons receive direct projections from catecholaminergic cell populations in the hindbrain and plays an important role in the regulation of intravascular volume. Clinical features of low cardiac output congestive heart failure (CHF) are a chronic accumulation of water and sodium, significant increases in plasma ANG II and aldosterone levels, and elevated SNA. Several studies demonstrate that central or peripheral blockade of ANG II or mineralocorticoid receptors and peripheral blockade of ANG II production leads to profound reductions in SNA. Thus, increases in circulating ANG II and/or plasma sodium appear to act at forebrain lamina terminalis neurons to increase SNA during CHF. The overall concept of the present proposal is that NM neurons projecting to the paraventricular nucleus of the hypothalamus integrate information regarding plasma ANG II levels, osmolality, and intravascular volume, and this integration is altered in rats with CHF. It is noteworthy that the cardiopulmonary reflex is attenuated in rats with CHF, and lesions of the NM attenuate several responses to changes in intravascular volume. Thus, CHF may be associated with reduced responsiveness of NM neurons to cardiopulmonary inputs thereby contributing to the increase in SNA observed in the presence of increased circulating ANG II. The proposed experiments will be performed in vivo using extracellular recordings to determine the integrated response of individual NM neurons to peripheral ANG II, osmotic, and cardiopulmonary receptor afferent input. The specific aims are: (1) determine whether individual NM neurons receive both peripheral ANG II and osmotic input and identify the receptors that mediate these responses, (2) determine whether osmo- or peripheral ANG II-sensitive NM neurons also receive cardiopulmonary input and whether these ascending inputs are mediated by noradrenergic receptor activation, (3) determine whether the basal activity and/or responses of NM neurons to these inputs are altered in rats with established CHF.