Salt-induced sympathoexcitation involves vasopressin V_1a receptor activation in the paraventricular nucleus of the hypothalamus

Abstract

-A high-salt diet can lead to hydromineral imbalance and increases in plasma sodium and osmolality. It is recognized as one of the major contributing factors for cardiovascular diseases such as hypertension. The paraventricular nucleus (PVN) plays a pivotal role in osmotically driven sympathoexcitation and high blood pressure, the precise mechanisms of which are not fully understood. Recent evidence indicates that AVP released from magnocellular neurons might be involved in this process. Using a combination of in vivo and in situ studies, we sought to investigate whether AVP, acting on PVN neurons, can change mean arterial pressure (MAP) and sympathetic nerve activity (SNA) in euhydrated male rats. Furthermore, we wanted to determine whether V 1a receptors on PVN neurons would be involved in saltinduced sympathoexcitation and hypertension. In rats, 4 days of salt loading (NaCl 2%) elicited a significant increase in plasma osmolality (39 Ϯ 7 mosmol/kgH 2O), an increase in MAP (26 Ϯ 2 mmHg, P Ͻ 0.001), and sympathoexcitation compared with euhydrated rats. Microinjection of AVP into the PVN of conscious euhydrated animals (100 nl, 3 M) elicited a pressor response (14 Ϯ 2 mmHg) and a significant increase in lumbar SNA (100 nl, 1 mM) (19 Ϯ 5%). Pretreatment with a V 1a receptor antagonist, microinjected bilaterally into the PVN of salt-loaded animals, elicited a decrease in lumbar SNA (Ϫ14 Ϯ 5%) and MAP (Ϫ19 Ϯ 5 mmHg), when compared with the euhydrated group. Our findings show that AVP plays an important role in modulating the salt-induced sympathoexcitation and high blood pressure, via V 1a receptors, within the PVN of male rats. As such, V 1a receptors in the PVN might contribute to neurogenic hypertension in individuals consuming a high-salt diet.vasopressin; paraventricular nucleus of the hypothalamus; salt loading; sympathoexcitation; hypertension A HIGH DIETARY INTAKE OF SALT is one of the major contributing factors to cardiovascular diseases, such as hypertension (11,12,32). High-salt diets can lead to a hydromineral imbalance and increases the plasma sodium concentrations and osmolality. This, in turn, can activate central hypothalamic nuclei that elevate sympathetic outflow and arterial blood pressure (BP), leading to a disorder referred to as salt-sensitive neurogenic hypertension (33).Osmotic perturbations are primarily sensed by osmosensing neurons located in brain regions that lack a blood-brain barrier termed circumventricular organs (CVOs). Under systemic hyperosmotic conditions, the CVOs are activated and send excitatory inputs to the paraventricular nucleus of the hypothalamus (PVN), an important integrative center involved in the autonomic and neuroendocrine functions to maintain body fluids and cardiovascular homeostasis (14,19,28). The PVN lies adjacent to the third ventricle in the anterior hypothalamus, and it is composed of magnocellular neurons (MCNs) and parvocellular neurons (PCN). The PCN send projections to autonomic nuclei, such as the rostral ventrolateral medulla (RVLM) and intermediola...

[Na+] Increases in Body Fluids Sensed by Central Nax Induce Sympathetically Mediated Blood Pressure Elevations via H+-Dependent Activation of ASIC1a

“…We compared the effects of mandatory HS ingestion between WT and Na x -KO mice using 2% NaCl, as previously reported in rats and mice by many groups (Choe et al, 2015;Ribeiro et al, 2015;Nicol et al, 2005): BP elevations were induced by the replacement of drinking water with 2% NaCl (HS ingestion). After HS ingestion for 7 days, [Na + ] levels in blood and CSF similarly increased to $160 mM from $145 mM in both genotypes (Figures 1A and 1B).…”

“…In addition to these mechanisms, elevations in plasma and CSF [NaCl] enhance sympathetic nerve activity (SNA), leading to increases in BP (Stocker et al, 2013). Animal studies demonstrated that the blockade of SNA strongly attenuated the BP elevations induced by a high salt (HS) intake or [Na + ] increases in body fluids (Kawano and Ferrario 1984;Ribeiro et al, 2015). An i.v.…”

Chronic high-sodium diet intake after weaning lead to neurogenic hypertension in adult Wistar rats

“…Adult Sprague-Dawley rats under moderate salt diet (2% NaCl) and chronic infusion of angiotensin II, which clamps circulating angiotensin II levels, develop high levels of blood pressure within days after infusion starts 15, 16 . Replacement of drinking water by sodium chloride solution results in high salt/water intake relation and also lead to hypertension in adult rats 12, 17 . One issue here is that none of the mentioned conditions are common in humans under high sodium intake and displaying high blood pressure.…”

Hypothalamic and inflammatory basis of hypertension

“…Indeed, increased AVP expression is critical in the maintenance of hypertension in several experimental models involving RAS hyperactivity (79, 84–86). Although the precise mechanisms by which excess AVP secretion drives high blood pressure remain an ongoing topic of discussion, several pathways may be implicated including sympathoexcitation via V 1a receptors in the PVN (87), brain RAS hyperactivity via V 2 receptors (88), and peripheral vasoconstriction via V 1 receptors (Figure 2) (82). …”