Hypertonic NaCl versus osmotic stimuli: distinct OVLT neurones can sense the difference to control sympathetic outflow and blood pressure

Despite large fluctuations in salt and water intake, mammals are able to maintain electrolyte concentrations, particularly sodium (Na⁺) as the major determinant of osmolality of the extracellular fluid (ECF), within narrow physiological limits (∼300 mOsm kg⁻¹). The two distinct sensory systems monitoring Na⁺ concentration and osmolality in the hypothalamic area of the brain are located outside the blood–brain barrier and are therefore known as circumventricular organs (CVOs).

The osmosensitive neurones of CVOs are located in the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT). Direct projections from these areas to hypothalamic nuclei containing neurosecretory magnocellular neurones promote the release of water‐conserving hormones such as arginine vasopressin (McKinley et al. 2001). Interestingly, these neurones also project to smaller parvocellular neurones located within other brain structures, such as the paraventricular nucleus of the hypothalamus (PVN) that modulate sympathetic nerve activity (SNA), an important mechanism in blood pressure (BP) homeostasis.

The distinct physiological responses to maintain fluid balance triggered by infusion of hypertonic sodium chloride (NaCl) and equi‐osmolar solutions have been debated for decades. McKinley and colleagues (1978) have shown that a peripheral osmoreceptor mechanism was most likely to be responsible for the thirst and antidiuresis induced by intracarotid infusion of hypertonic NaCl or sucrose in sheep. However, they also found support for a periventricular Na⁺ receptor mechanism because of differential drinking responses to intracerebroventricular (i.c.v.) administration of hypertonic NaCl or sucrose.

The SFO seems to be the primary locus of NaCl sensing for the control of salt‐intake behaviour at the central level, identified as a sensory mechanism that relies on activation of a Na⁺ channel (Na_x); it is not osmosensing (Hyiama et al. 2004). The SFO is also involved in mediating the central Na⁺‐induced pressor response, since administration of NaCl‐rich artificial cerebrospinal fluid (aCSF) into the SFO caused an increase in BP, which was blunted by an angiotensin II type 1 (AT1) receptor antagonist at the same site. However, equi‐osmotic infusion of manitol did not change BP, indicating that the pressor response is Na⁺ specific and not due to osmolality or volume effects (Tiruneh et al. 2013). Not only SFO, but also OVLT neurones are capable of detecting extracellular NaCl concentration and altering the sympathetic nerve discharge in order increase BP (Kinsman et al. 2017b). However, to date, no study has been able to show whether distinct cellular processes of osmosensitive neurones can differentiate between hyperosmolality versus hypertonic NaCl stimulus to selectively control SNA and BP.

In this issue of The Journal of Physiology, Kinsman and co‐workers (2017a) addressed this important issue by performing an elegant in vivo neurophysiological study. They determined how subsets of OVLT neurones respond differentially to hypertonic NaCl versus osmolality and subsequently regulate the sympathetic nervous system. More precisely, they showed that local injection of hypertonic saline into the OVLT produced an increase in SNA and BP, whereas an equi‐osmotic stimulus of mannitol/sorbitol solutions had no effect. Moreover, these authors combined in vitro whole‐cell recordings to demonstrate that stimulation with hypertonic saline caused the discharge frequency of OVLT neurones to increase, unlike stimulation with the equi‐osmotic mannitol solution.

These findings by Kinsman and colleagues (2017a) open several interesting perspectives for further investigation regarding the functional significance of distinct cellular responses of Na⁺ and osmosensitive OVLT neurones: (i) What are the physiological mechanisms, phenotype and neurotransmitters released by the functionally distinct OVLT neurones? (ii) How do these differences translate to hypertonic NaCl and osmotically driven sympathetic responses and BP control? (iii) Do salt‐sensitive rats (e.g. Dahl‐Salt) show alterations in OVLT neuronal populations that control hydroelectrolytic balance, sympathetic hyperactivity and hypertension in response to high salt diet? (iv) It would be interesting to determine the contribution of the SFO compared to the OVLT to the sympathetic responses to hypertonic saline and osmolality challenges.

Understanding the characteristics of the CVO neurones relating to control of body fluid and cardiovascular homeostasis in response to distinct osmotic stimuli will require a range of techniques from anatomical, molecular, biochemical and pharmaco/opto‐genetic tools, and this paper by Kinsman and co‐workers (2017a) is a great kick‐off in elucidating the complex hierarchy and mechanisms of the osmoregulatory signalling network at the CNS level.

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Competing interests

None declared.