Previous studies have reported that chronic increases in dietary salt intake enhance sympathetic nerve activity (SNA) and arterial blood pressure (ABP) responses evoked from brainstem nuclei of normotensive, salt-resistant rats. The purpose of the present study was to determine whether this sensitization results in exaggerated SNA and ABP responses during activation of various cardiovascular reflexes and also increases ABP variability (BPV). Male Sprague-Dawley rats were fed 0.1% NaCl chow (low), 0.5% NaCl chow (medium), 4.0% NaCl chow (high) for 14–17 days. Then, animals were prepared for recordings of lumbar, renal, and splanchnic SNA and ABP. The level of dietary salt intake directly correlated with the magnitude of SNA and ABP responses to electrical stimulation of sciatic afferents or intracerebroventricular infusion of 0.6M or 1.0M NaCl. Similarly, there was a direct correlation between the level of dietary salt intake and the sympathoinhibitory responses produced by acute volume expansion, stimulation of the aortic depressor nerve or cervical vagal afferents. In contrast, dietary salt intake did not affect the sympathetic and ABP responses to chemoreflex activation produced by hypoxia or hypercapnia. Chronic lesion of the anteroventral 3rd ventricle region eliminated the ability of dietary salt intake to modulate these cardiovascular reflexes. Finally, rats chronically instrumented with telemetry units indicate that increased dietary salt intake elevated BPV but not mean ABP. These findings indicate that dietary salt intake works through the forebrain hypothalamus to modulate various centrally-mediated cardiovascular reflexes and increase BPV.

High salt diet elevates NaCl concentrations in the cerebrospinal fluid to increase sympathetic nerve activity (SNA) in salt-sensitive hypertension. The organum vasculosum of the lamina terminalis (OVLT) resides along the rostral wall of the third ventricle, lacks a complete blood-brain-barrier, and plays a pivotal role in body fluid homeostasis. Therefore, the present study used a multi-faceted approach to examine whether OVLT neurons of Sprague Dawley rats are intrinsically sensitive to changes in extracellular NaCl concentrations and mediate the sympathoexcitatory responses to central NaCl loading. Using in vitro whole-cell recordings, step-wise increases in extracellular NaCl concentrations (2.5–10mM) produced concentration-dependent excitation of OVLT neurons. Additionally, these excitatory responses were intrinsic to OVLT neurons as hypertonic NaCl evoked inward currents despite pharmacologic synaptic blockade. In vivo single-unit recordings demonstrate the majority of OVLT neurons (72%, 13/19) display concentration-dependent increases in neuronal discharge to intracarotid (50µL/15s) or intracerebroventricular infusion (5µL/10min) of hypertonic NaCl. Microinjection of hypertonic NaCl (30nL/60s) into the OVLT, but not adjacent areas, increased lumbar SNA, adrenal SNA, and ABP in a concentration-dependent manner. Renal SNA decreased, and splanchnic SNA remained unaffected. Finally, local inhibition of OVLT neurons with the GABAA receptor agonist muscimol (24nL/10s) significantly attenuated the sympathoexcitatory and pressor responses to intracerebroventricular infusion of 0.5M or 1.0M NaCl. Collectively, these findings indicate that OVLT neurons detect changes in extracellular NaCl concentrations to selectively alter SNA and raise ABP.

Elevated NaCl concentrations of the cerebrospinal fluid (CSF) increase sympathetic nerve activity (SNA) in salt-sensitive hypertension. Neurons of the rostral ventrolateral medulla (RVLM) play a pivotal role in the regulation of SNA and receive mono- or poly-synaptic inputs from several hypothalamic structures responsive to hypernatremia. Therefore, the present study investigated the contribution of RVLM neurons to the SNA and pressor response to CSF hypernatremia. Lateral ventricle infusion of 0.15M, 0.6M, and 1.0M NaCl (5µL/10 min) produced concentration-dependent increases in lumbar SNA, adrenal SNA, and arterial blood pressure (ABP) despite no change in splanchnic SNA and a decrease in renal SNA. Ganglionic blockade with chlorisondamine or acute lesion of the lamina terminalis blocked or significantly attenuated these responses, respectively. RVLM microinjection of the GABAA agonist muscimol abolished the sympathoexcitatory response to ICV infusion of 1M NaCl. Furthermore, blockade of ionotropic glutamate, but not angiotensin II type 1, receptors significantly attenuated the increase in lumbar SNA, adrenal SNA, and ABP. Finally, single-unit recordings of spinally-projecting RVLM neurons revealed three distinct populations based on discharge responses to ICV infusion of 1M NaCl: Type I excited (46%, 11/24), Type II inhibited (37%, 9/24), and Type III no change (17%, 4/24). All neurons with slow conduction velocities were Type I cells. Collectively, these findings suggest that acute increases in CSF NaCl concentrations selectively activate a discrete population of RVLM neurons through glutamate receptor activation to increase SNA and ABP.