[Show abstract][Hide abstract] ABSTRACT: Autonomic and endocrine profiles of chronic hypertension and heart failure resemble those of acute dehydration. Importantly, all of these conditions are associated with exaggerated sympathetic nerve activity (SNA) driven by glutamatergic activation of the hypothalamic paraventricular nucleus (PVN). Here, studies sought to gain insight into mechanisms of disease by determining the role of PVN ionotropic glutamate receptors in supporting SNA and mean arterial pressure (MAP) during dehydration and by elucidating mechanisms regulating receptor activity. Blockade of PVN NMDA receptors reduced (P<0.01) renal SNA and MAP in urethane-chloralose anesthetized dehydrated (DH) (48 h water deprivation) rats, but had no effect in euhydrated (EH) controls. Blockade of PVN AMPA receptors had no effect in either group. NMDA in PVN caused dose-dependent increases of renal SNA and MAP in both groups, but the Emax renal SNA response was greater (P<0.05) in DH rats. The latter was not explained by increased PVN expression of NMDA receptor NR1 subunit protein, increased PVN neuronal excitability, or decreased brain water content. Interestingly, PVN injection of the pan-specific excitatory amino acid transporter (EAAT) inhibitor TBOA produced smaller sympathoexcitatory and pressor responses in DH rats, which was associated with reduced glial expression of EAAT2 in PVN. Like chronic hypertension and heart failure, dehydration increases excitatory NMDA receptor tone in PVN. Reduced glial-mediated glutamate uptake was identified as a key contributing factor. Defective glutamate uptake in PVN could therefore be an important, but as yet unexplored, mechanism driving sympathetic hyperactivity in chronic cardiovascular diseases.
[Show abstract][Hide abstract] ABSTRACT: Neurons of the rostral ventrolateral medulla (RVLM) are critical for generating and regulating sympathetic nerve activity (SNA). Systemic administration of angiotensin II (Ang II) combined with a high salt diet induces hypertension that is postulated to involve elevated SNA. However, a functional role for RVLM vasomotor neurons in Ang II-salt hypertension has not been established. Here, we tested the hypothesis that RVLM vasomotor neurons have exaggerated resting discharge in rats with Ang II-salt hypertension. Rats in the hypertensive (HT) group consumed a high salt (2% NaCl) diet and received an infusion of Ang II (150 ng kg(-1) min(-1), sc) for 14 days. Rats in the normotensive (NT) group consumed a normal salt (0.4% NaCl) diet and were infused with normal saline. Telemetric recordings in conscious rats revealed that mean arterial pressure (MAP) was significantly increased in HT compared to NT rats (P<0.001). Under anesthesia (urethane/chloralose), MAP remained elevated in HT compared to NT rats (P<0.01). Extracellular single unit recordings in HT (n=28) and NT (n=22) rats revealed that baro-sensitive RVLM neurons in both groups (HT: 23 cells, NT: 34 cells) had similar cardiac rhythmicity and resting discharge. However, a greater (P<0.01) increase of MAP was needed to silence discharge of neurons in HT (17 cells, 44 ± 4.9 mmHg) than NT (28 cells, 29 ± 3 mmHg) rats. Maximum firing rates during arterial baroreceptor unloading were similar across groups. We conclude that heightened resting discharge of sympathoexcitatory RVLM neurons is not required for maintenance of neurogenic Ang II-salt hypertension.
[Show abstract][Hide abstract] ABSTRACT: Like humans with sleep apnea (SA), rats exposed to chronic intermittent hypoxia (CIH) experience arterial hypoxemias and develop hypertension characterized by exaggerated sympathetic nerve activity (SNA). To gain insight into poorly understood mechanisms that initiate SA/CIH-associated hypertension, studies were performed in rats exposed to CIH for only 7 days. Compared to sham-treated normoxic controls, CIH exposed rats had significantly increased hematocrit (P<0.001) and mean arterial pressure (MAP, P<0.05) (n=8/group). Blockade of ganglionic transmission caused a significantly (P<0.05) greater reduction of MAP in rats exposed to CIH than controls (n=8/group), indicating a greater contribution of SNA in support of MAP even at this early stage of CIH hypertension. Chemical inhibition of neuronal discharge in the hypothalamic paraventricular nucleus (PVN) (muscimol,100 pmol) had no effect on renal SNA, but reduced lumbar SNA (P<0.005) and MAP (P<0.05) more in CIH exposed rats (n=8) than controls (n=7), indicating that CIH increased the contribution of PVN neuronal activity in the support of lumbar SNA and MAP. Because CIH activates brain regions controlling body fluid homeostasis, effects of internal carotid artery injection of hypertonic saline were tested and determined to increase lumbar SNA more (P<0.05) in CIH exposed rats than controls (n=9/group). We conclude that neurogenic mechanisms are activated early in the development of CIH hypertension such that elevated MAP relies on increased sympathetic tonus and ongoing PVN neuronal activity. Increased sensitivity of sodium/osmo-sensitive circuitry in CIH exposed rats suggests that early neuroadaptive responses among body fluid regulatory neurons could contribute to initiation of CIH hypertension.
[Show abstract][Hide abstract] ABSTRACT: Exposure to chronic intermittent hypoxia (CIH) is an animal model that mimics repetitive bouts of hypoxemia experienced by humans with sleep apnea. Rats exposed to CIH develop hypertension that depends on activation of sympathetic nerve activity (SNA). Since obesity and metabolic syndrome have been linked to neurogenic hypertension and sleep apnea, and because sleep apnea can adversely affect aerobic exercise capacity, we tested the hypothesis that rats bred for selection of low aerobic capacity running (LCR) would have a greater hypertensive response to CIH than rats bred for high aerobic capacity running (HCR). Blockade of ganglionic transmission was performed to compare the contribution of SNA to maintenance of resting mean arterial pressure (MAP). Next, hypertensive responses to 7 days of CIH were compared across LCR and HCR rats (14-16 months old). Lastly, contribution of the hypothalamic paraventricular nucleus (PVN) to maintenance of SNA and hypertension following CIH was determined and compared across groups. Although LCR rats were less active and had greater body weight than HCR rats, resting MAP, contribution of ongoing SNA to maintenance of MAP, and hypertensive responses to CIH were similar between groups. Contrary to our hypothesis, chemical inhibition of PVN with muscimol (1 mmol/100 nl) caused a larger fall of MAP in HCR than LCR rats. We conclude that rats with low aerobic capacity do not have resting hypertension or an exaggerated hypertensive response to CIH. Interestingly, maintenance of CIH hypertension in LCR rats compared to HCR rats appears less reliant on ongoing PVN neuronal activity.
[Show abstract][Hide abstract] ABSTRACT: Although evidence indicates that activation of presympathetic paraventricular nucleus (PVN) neurons contributes to the pathogenesis of salt-sensitive hypertension, the underlying cellular mechanisms are not fully understood. Recent evidence indicates that small conductance Ca(2+)-activated K(+) (SK) channels play a significant role in regulating the excitability of a key group of sympathetic regulatory PVN neurons, those with axonal projections to the rostral ventrolateral medulla (RVLM; i.e., PVN-RVLM neurons). In the present study, rats consuming a high salt (2% NaCl) diet were made hypertensive by systemic infusion of angiotensin II (AngII), and whole cell patch-clamp recordings were made in brain slice from retrogradely labeled PVN-RVLM neurons. To determine if the amplitude of SK current was altered in neurons from hypertensive rats, voltage-clamp recordings were performed to isolate SK current. Results indicate that SK current amplitude (P < 0.05) and density (P < 0.01) were significantly smaller in the hypertensive group. To investigate the impact of this on intrinsic excitability, current-clamp recordings were performed in separate groups of PVN-RVLM neurons. Results indicate that the frequency of spikes evoked by current injection was significantly higher in the hypertensive group (P < 0.05-0.01). Whereas bath application of the SK channel blocker apamin significantly increased discharge of neurons from normotensive rats (P < 0.05-0.01), no effect was observed in the hypertensive group. In response to ramp current injections, subthreshold depolarizing input resistance was greater in the hypertensive group compared with the normotensive group (P < 0.05). Blockade of SK channels increased depolarizing input resistance in normotensive controls (P < 0.05) but had no effect in the hypertensive group. On termination of current pulses, a medium afterhyperpolarization potential (mAHP) was observed in most neurons of the normotensive group. In the hypertensive group, the mAHP was either small or absent. In the latter case, an afterdepolarization potential (ADP) was observed that was unaffected by apamin. Apamin treatment in the normotensive group blocked the mAHP and revealed an ADP resembling that seen in the hypertensive group. We conclude that diminished SK current likely underlies the absence of mAHPs in PVN-RVLM neurons from hypertensive rats. Both the ADP and greater depolarizing input resistance likely contribute to increased excitability of PVN-RVLM neurons from rats with AngII-Salt hypertension.
Journal of Neurophysiology 11/2010; 104(5):2329-37. DOI:10.1152/jn.01013.2009 · 2.89 Impact Factor