Exaggerated sympathetic nervous system activity is a major contributor to the pathogenesis of congestive heart failure (CHF). Two factors appear critical in producing the sympathoexcitatory state. First, an elevated level of plasma angiotensin II (ANG II) in CHF acts within the brain to increase sympathetic nerve activity (SNA). Second, chronic extracellular fluid accumulation reduces cardiopulmonary reflex function and thus inhibitory restraint of SNA. These findings are key to the present proposal because neurons in the hypothalamic paraventricular nucleus (PVN) are required for both the sympathoexcitatory actions of elevated ANG II as well as the sympathoinhibitory effects of volume expansion. Experiments will be performed in rats with CHF induced by ligating the left anterior descending coronary artery and in sham-operated control rats. We will test the hypothesis that sympathetic hyperactivity in CHF results from increased ANG II-mediated synaptic input to the PVN and that this has an enhanced excitatory effect due to a concurrent reduction in GABA-mediated cardiopulmonary reflex inhibition.
In Aim 1, effects of acute GABA-A and ANG II AT1 receptor blockade in the PVN on the level of ongoing renal and lumbar SNA will be determined. Effects will be compared among rats with graded levels of CHF. Studies will also determine how SNA responses to physiological activation of ANG II and GABA inputs to the PVN are altered in CHF.
In Aim 2, we will record the response of individual RVLM-, IML- and NTS-projecting PVN neurons to activation of volume-/mechanosensitive cardiopulmonary inputs and ANG II-sensitive inputs in vivo. We anticipate that PVN unit responses to cardiopulmonary input will be significantly attenuated in CHF. This, in turn, is postulated to leave sympathoexcitatory effects of central ANG II relatively unopposed. Therefore, we expect ANG II effects on SNA and PVN unit discharge to be enhanced.
In Aim 3, brain slices will be prepared and whole cell patch-clamp recordings will be performed in vitro from PVN neurons retrogradely labelled from the RVLM, IML and NTS. We will determine how the amplitude and frequency of synaptic activity are altered in each cell group in CHF. We will determine interactions between ANG II and GABA inputs in regulating PVN neuronal excitability and how these are altered in CHF. Finally, we will also determine how postsynpatic depolarization, discharge and inward current responses to ANG II are altered in CHF. The proposed studies are the first to examine mechanisms of synaptic plasticity in CHF among identified sympathetic-regulatory neurons. This information will yeild new and potentially important insight into the processes that lead to sympathetic activation and progression of disease severity in CHF.
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