Forebrain Neurohumoral Integration in Heart Failure

描述（由申请人提供）：循环血管紧张素II （ANG II）和血浆渗透压升高使包括中隔核（NM或正中视前核）在内的前脑终末层神经元兴奋，并增加交感神经活动（SNA）。此外，NM神经元接受后脑儿茶酚胺能细胞群的直接投射，并在血管内体积的调节中发挥重要作用。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积累，血浆ANG II和醛固酮水平显著升高，SNA升高。一些研究表明，中枢或外周阻断ANG II或矿皮质激素受体以及外周阻断ANG II的产生会导致SNA的显著降低。因此，循环ANG II和/或血浆钠的增加似乎在CHF期间作用于前脑终末层神经元以增加SNA。目前提出的总体概念是，投射到下丘脑室旁核的NM神经元整合了有关血浆ANG II水平、渗透压和血管内体积的信息，而这种整合在CHF大鼠中发生了改变。值得注意的是，CHF大鼠的心肺反射减弱，NM病变减弱了对血管内容积变化的几种反应。因此，CHF可能与NM神经元对心肺输入的反应性降低有关，从而导致在循环ANG II增加的情况下观察到的SNA增加。拟议的实验将在体内进行，使用细胞外记录来确定单个NM神经元对外周ANG II、渗透和心肺受体传入输入的综合反应。具体目的是：(1)确定单个NM神经元是否同时接受外周ANG II和渗透输入，并确定介导这些反应的受体；(2)确定渗透或外周ANG II敏感的NM神经元是否也接受心肺输入，以及这些上升输入是否由去甲肾上腺素能受体激活介导；(3)确定在已建立CHF的大鼠中，NM神经元对这些输入的基础活性和/或反应是否发生改变。

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.