Aldosterone-Sensitive Nucleus Tractus Solitarius Neurons Regulate Sensitivity of the Baroreceptor Reflex in High Sodium–Loaded Rats

Abstract

Baroreceptor and chemoreceptor signals are transmitted to the nucleus tractus solitarius (NTS) via the primary afferent fibers of the glossopharyngeal and vagal nerves, suggesting a role for the NTS in modulating the arterial baroreceptor reflex (baroreflex). The NTS contains numerous neurotransmitters and receptors, including glutamate, GABA, or substance P (1). However, the role of these neurotransmitters in regulatory baroreceptor and chemoreceptor signals is not fully understood. Recently, the enzyme 11β-hydroxysteroid dehydrogenase type 2 (HSD2) and the mineralocorticoid receptors (MR) were identified in the NTS along with common neurotransmitters; such neurons are termed 'aldosterone-sensitive HSD2 neurons' (2 -5). Furthermore, a number of studies have shown that the aldosterone-sensitive HSD2 neurons in the NTS are involved in sodium appetite or in regulation of body fluid circulation as they are selectively activated by sodium deficiency (2, 4).Aldosterone is secreted from the adrenal cortex in response to sodium deficiency and also amplifies sodium intake. A cardiovascular role for aldosterone has been suggested from the evidence of MR expression in vascular tissues, including the heart. Furthermore, some studies have reported a role for aldosterone in the baroreflex response. For example, both acute and chronic peripheral aldosterone administration impaired baroreceptor responses in dogs (6) and in humans (7). In addition, central infusion of sodium-enriched artificial cerebrospinal fluid (aCSF) caused increased aldosterone and corticosterone levels in the hypothalamus and impaired baroreceptor function (8, 9), suggesting a role for central aldosterone in baroreflex function. However, the role of aldosteronesensitive neurons in the NTS in baroreflex responses remains unclear.In the present study, we tested the hypothesis that the aldosterone-sensitive neurons in the NTS regulate the baroreflex function. To address this hypothesis, we examined the baroreflex sensitivity induced by phenylephrine in high sodium-loaded rats.Male Wistar rats (180 -200 g) were purchased from Kyudo (Kumamoto). The animals were maintained at 24 ± 2°C with a 12-h light-dark cycle (light on at 07:00 Medicine, Kyoto 602-8566, Japan Received December 25, 2009; Accepted February 19, 2010 Abstract. We examined the role of aldosterone-sensitive neurons in the nucleus tractus solitarius (NTS) in the arterial baroreceptor reflex (baroreflex) function. Baroreflex sensitivity was induced by phenylephrine in high sodium-loaded rats and was significantly reduced. This baroreflex sensitivity was reversed by microinjection of the mineralocorticoid receptor (MR) antagonist eplerenone into the NTS. 11β-Hydroxysteroid dehydrogenase type 2 neurons and MR were also identified in the NTS. These data suggest that the aldosterone-sensitive neurons in the NTS may have an important role in baroreflex function.

Mineralocorticoid Receptor-Dependent Impairment of Baroreflex Contributes to Hypertension in a Mouse Model of Primary Aldosteronism

“…Based on the present effect of central MRs, the neurogenic component is partly responsible for MR-dependent dysautonomia and impaired baroreflex in TASK −/− mice. This notion is also reinforced by prior reports demonstrating that the central Aldo/MR signaling plays an important role in regulation of sympathetic drive and baroreflex in the NTS, rostral ventrolateral medulla, and hypothalamic paraventricular nucleus (Masuda et al, 2010; Nakagaki et al, 2012; Zhang et al, 2012; Lincevicius et al, 2015). Due to lack of experimental data in the present study, the contribution of peripheral MRs is not excluded.…”

“…Despite the evidence of contribution of G protein-coupled estrogen receptor activation to the non-genomic effects of Aldo (Brailoiu et al, 2013), the majority of Aldo’s effects are exerted through the activation of the mineralocorticoid receptor (MR) (Hermidorff et al, 2017). Accumulated evidence has implicated the importance of Aldo/MR signaling in the pathogenesis of different hypertensive models, including renovascular hypertension (Lincevicius et al, 2015), stroke-prone spontaneous hypertension (Nakagaki et al, 2012) and high salt-loaded hypertension (Masuda et al, 2010). Chronic systemic administration of Aldo/deoxycorticosterone (DOC) elevated arterial pressure in several animal models (Garwitz and Jones, 1982; Chen et al, 1989; Xue et al, 2012).…”

Aldosterone infusion into the 4th ventricle produces sodium appetite with baroreflex attenuation independent of renal or blood pressure changes

“…However, no study investigated if aldosterone acting in the hindbrain changes arterial pressure, particularly at the dose that it produces sodium appetite. Studies showing that the MR antagonist spironolactone increased baroreceptor reflex sensitivity in a renovascular hypertension model or that injection of the MR antagonist eplerenone into the NTS increased baroreflex sensitivity in salt-loaded rats suggest that endogenous aldosterone or corticosterone may be involved in the control of baroreflex function (Lincevicius et al, 2015;Masuda et al, 2010).…”

Aldosterone is synthesized in and activates bulbospinal neurons through mineralocorticoid receptors and ENaCs in the RVLM

“…In the brainstem, neurons that contain hydroxysteroid dehydrogenase 2 and MRs were present in the nucleus tractus solitarius. 8 In the rostral ventrolateral medulla (RVLM), Zhu et al 9 and Nakagaki et al 10 reported that microinjection of aldosterone into the RVLM increased blood pressure.…”