Activation of the hypothalamic paraventricular nucleus by forebrain hypertonicity selectively increases tonic vasomotor sympathetic nerve activity

Abstract

We recently reported that mean arterial pressure (MAP) is maintained in water-deprived rats by an irregular tonic component of vasomotor sympathetic nerve activity (SNA) that is driven by neuronal activity in the hypothalamic paraventricular nucleus (PVN). To establish whether generation of tonic SNA requires time-dependent (i.e., hours or days of dehydration) neuroadaptive responses or can be abruptly generated by even acute circuit activation, forebrain sympathoexcitatory osmosensory inputs to PVN were stimulated by infusion (0.1 ml/min, 10 min) of hypertonic saline (HTS; 1.5 M NaCl) through an internal carotid artery (ICA). Whereas isotonic saline (ITS; 0.15 M NaCl) had no effect (n = 5), HTS increased (P < 0.001; n = 6) splanchnic SNA (sSNA), phrenic nerve activity (PNA), and MAP. Bilateral PVN injections of muscimol (n = 6) prevented HTS-evoked increases of integrated sSNA and PNA (P < 0.001) and attenuated the accompanying pressor response (P < 0.01). Blockade of PVN NMDA receptors with d-(2R)-amino-5-phosphonovaleric acid (AP5; n = 6) had similar effects. Analysis of respiratory rhythmic bursting of sSNA revealed that ICA HTS increased mean voltage (P < 0.001) without affecting the amplitude of inspiratory or expiratory bursts. Analysis of cardiac rhythmic sSNA likewise revealed that ICA HTS increased mean voltage. Cardiac rhythmic sSNA oscillation amplitude was also increased, which is consistent with activation of arterial baroreceptor during the accompanying pressor response. Increased mean sSNA voltage by HTS was blocked by prior PVN inhibition (muscimol) and blockade of PVN NMDA receptors (AP5). We conclude that even acute glutamatergic activation of PVN (i.e., by hypertonicity) is sufficient to selectively increase a tonic component of vasomotor SNA.

ATP stimulates rat hypothalamic sympathetic neurons by enhancing AMPA receptor-mediated currents

“…Moreover, NMDA receptors have been shown by other groups to contribute to PVN regulation of sympathetic outflow in response to a hyperosmotic stimulation (Bardgett et al 2014;Holbein and Toney 2015;Jin et al 2001). In a recent publication from our group, however, we found that ATP-mediated effects on sympathoexcitatory PVN responses involved AMPA (but not NMDA) receptors (Ferreira-Neto et al 2013).…”

Glutamatergic neurons of the paraventricular nucleus are critical contributors to the development of neurogenic hypertension

“…During periods of prolonged exposure to high‐salt diets, dehydration and stressors, animals and humans show an increase in BP (Vivas et al . ; Holbein & Toney, ). Salt‐sensing and thirst are both mediated either directly or indirectly by the PVN or areas that are relaying that information to the PVN (e.g.…”

Carotid bodies contribute to sympathoexcitation induced by acute salt overload

“…Hyperosmotic challenges caused by salt overload or dehydration (water deprivation) are sensed centrally and evoke increases in sympathetic nervous activity (SNA; Antunes, Yao, Pickering, Murphy, & Paton, ; Colombari et al., , ; Holbein & Toney, , ; Kinsman, Browning, & Stocker, ; Kinsman, Simmonds, Browning, & Stocker, ; Shi, Stocker, & Toney, ). This response depends on specialized cells that are located in the organum vasculosum of the lamina terminalis (OVLT) and the subfornical organ and that detect changes in extracellular osmolality intrinsically (Anderson, Washburn, & Ferguson, ; Kinsman, et al., ).…”

“…In contrast, hypothalamic areas are considered to be the primary site for evoking an increase in the sympathetic and respiratory activities during hyperosmotic stimulation (Antunes et al., ; Holbein & Toney, ; Kinsman et al., , b; Shi et al., ). According to Holbein and Toney (), the bilateral inhibition of hypothalamic paraventricular nucleus (PVN) neurons with muscimol prevented hyperosmotic NaCl‐evoked increases of splanchnic SNA and phrenic nerve activity (PNA).…”

“…In contrast, hypothalamic areas are considered to be the primary site for evoking an increase in the sympathetic and respiratory activities during hyperosmotic stimulation (Antunes et al., ; Holbein & Toney, ; Kinsman et al., , b; Shi et al., ). According to Holbein and Toney (), the bilateral inhibition of hypothalamic paraventricular nucleus (PVN) neurons with muscimol prevented hyperosmotic NaCl‐evoked increases of splanchnic SNA and phrenic nerve activity (PNA). Usually, central hyperosmolality is abruptly induced by rapid injections of hyperosmotic NaCl, either intracerebroventricular or via the internal carotid artery (Holbein & Toney, ; Kinsman et al., , b; Shi et al., ), without activation of carotid bodies.…”