Organum Vasculosum of the Lamina Terminalis Detects NaCl to Elevate Sympathetic Nerve Activity and Blood Pressure

Abstract

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.

Putative Mechanism of Salt-Dependent Neurogenic Hypertension

“…By analogy with the work on the SFO, the Na x –dependent excitation of MnPO neurons could well be of a paracrine nature. This mode of intercellular communication is TTX-resistant and therefore compatible with Kinsman et al’s results in the OVLT 3 . In sum, the response of OVLT neurons to extracellular NaCl and the resulting autonomic effects could result from a direct effect of hyperosmolarity on these neurons or they could represent a paracrine response to [Na + e ] mediated by glial Na x .…”

“…In conscious humans, hyperosmotic stimuli elevate BP and sympathetic tone 2 and this particular neurogenic response likely contributes to salt-dependent hypertension. In this issue of Hypertension, Kinsman et al 3 suggest that the autonomic nervous system effects elicited by systemic hypernatremia result from a direct action of [NaCl] on neurons located within the organum vasculosum laminae terminalis (OVLT).…”

“…Kinsman et al 3 demonstrate that, in tissue slices, 56% of OVLT neurons are vigorously activated by low-grade hyperosmotic hypernatremia (2.5 to 10mM increase in [NaCl e ]). The inward (depolarizing) current produced by raising [NaCl e ] in vitro persisted under conditions of reduced synaptic transmission (TTX plus blockers of ionotropic glutamate and GABA receptors) suggesting that OVLT neurons could be intrinsically sensitive to hypernatremia.…”

“…Regardless of the precise mechanism by which hyperosmotic hypernatremia activates OVLT neurons, a key question addressed by Kinsman et al 3 is whether these neurons respond to physiologically relevant changes in plasma [NaCl] in vivo . This is indeed the case: most OVLT neurons (72%) were vigorously activated by injecting NaCl into the carotid artery or a lateral ventricle in a dosage range that raises [Na + e ] modestly (estimate: 3–8mM).…”

“…NaCl injection into the OVLT changed sympathetic nerve activity (SNA) in a regionally specific manner 3 . These results show that a minimal rise in [NaCl e ] within the OVLT is sufficient to increase BP, probably by increasing SNA to muscle and skin arterioles, whilst facilitating renal sodium excretion by withdrawing renal sympathetic tone.…”