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. ? ?
