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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL073661-01
Application #
6648171
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Commarato, Michael
Project Start
2003-05-01
Project End
2006-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
1
Fiscal Year
2003
Total Cost
$41,608
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Physiology
Type
Other Domestic Higher Education
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Stocker, Sean D; Toney, Glenn M (2007) Vagal afferent input alters the discharge of osmotic and ANG II-responsive median preoptic neurons projecting to the hypothalamic paraventricular nucleus. Brain Res 1131:118-28
Shi, Peng; Stocker, Sean D; Toney, Glenn M (2007) Organum vasculosum laminae terminalis contributes to increased sympathetic nerve activity induced by central hyperosmolality. Am J Physiol Regul Integr Comp Physiol 293:R2279-89
Stocker, Sean D; Wilson, Melinda E; Madden, Christopher J et al. (2006) Intravenous 6-hydroxydopamine attenuates vasopressin and oxytocin secretion stimulated by hemorrhage and hypotension but not hyperosmolality in rats. Am J Physiol Regul Integr Comp Physiol 291:R59-67
Stocker, Sean D; Simmons, Johnny R; Stornetta, Ruth L et al. (2006) Water deprivation activates a glutamatergic projection from the hypothalamic paraventricular nucleus to the rostral ventrolateral medulla. J Comp Neurol 494:673-85
Stocker, Sean D; Hunwick, Kimberly J; Toney, Glenn M (2005) Hypothalamic paraventricular nucleus differentially supports lumbar and renal sympathetic outflow in water-deprived rats. J Physiol 563:249-63
Stocker, Sean D; Toney, Glenn M (2005) Median preoptic neurones projecting to the hypothalamic paraventricular nucleus respond to osmotic, circulating Ang II and baroreceptor input in the rat. J Physiol 568:599-615
Stocker, Sean D; Keith, Kimberly J; Toney, Glenn M (2004) Acute inhibition of the hypothalamic paraventricular nucleus decreases renal sympathetic nerve activity and arterial blood pressure in water-deprived rats. Am J Physiol Regul Integr Comp Physiol 286:R719-25