Cardiac sympathetic afferent stimulation induces salt-sensitive sympathoexcitation through hypothalamic epithelial Na⁺ channel activation

Abstract

The cardiac sympathetic afferent (CSA), which plays an important role in heart-brain communication for sympathoexcitation, is stimulated in heart failure. Additionally, high salt intake leads to further sympathoexcitation due to activation of hypothalamic epithelial Na(+) channels (ENaCs) in heart failure. In the present study, we stimulated the CSA in adult male mice by epicardial application of capsaicin and using ethanol as a control to determine whether CSA stimulation led to activation of hypothalamic ENaCs, resulting in salt-induced sympathoexcitation. Three days after capsaicin treatment, an upregulation of hypothalamic α-ENaCs, without activation of mineralocorticoid receptors, was observed. We also examined expression levels of the known ENaC activator TNF-α. Hypothalamic TNF-α increased in capsaicin-treated mice, whereas intracerebroventricular infusion of the TNF-α blocker etanercept prevented capsaicin-induced upregulation of α-ENaCs. To examine brain arterial pressure (AP) sensitivity toward Na(+), we performed an intracerebroventricular infusion of high Na(+)-containing (0.2 M) artificial cerebrospinal fluid. AP and heart rate were significantly increased in capsaicin-treated mice compared with control mice. CSA stimulation also caused excitatory responses with high salt intake. Compared with a regular salt diet, the high-salt diet augmented AP, heart rate, and 24-h urinary norepinephrine excretion, which is an indirect marker of sympathetic activity with mineralocorticoid receptor activation, in capsaicin-treated mice but not in ethanol-treated mice. Treatment with etanercept or the ENaC blocker benzamil prevented these salt-induced excitatory responses. In summary, we show that CSA stimulation leads to an upregulation of hypothalamic α-ENaCs mediated via an increase in TNF-α and results in increased salt sensitivity.

Cellular and Molecular Mechanisms Underlying Arterial Baroreceptor Remodeling in Cardiovascular Diseases and Diabetes

“…ENaCs were first identified as mechanosensory in Caenorhabditis elegans [121][122][123]. Four subunits of ENaCs (a-, b-, c-, and r-ENaC) are expressed in many tissues, including brain, kidney, and aortic baroreceptors [124][125][126][127][128][129]. In polarized epithelial cells, they function as an obligate heteromultimer to direct the flow of Na ?…”

The Gut, Its Microbiome, and Hypertension

“…GM-mediated synthesis of steroids that reduce the inactivation of cortisol by acting as inhibitors of 11ß-hydroxysteroid dehydrogenase 2 (11HSD2) have also been described [ 58 ]. These two types of steroids produced by the GM have potential to be prohypertensive through local actions in the gut and, being freely diffusible, the brain [ 59 , 60 , 61 ] and kidney. Further, metabolic activity of the GM may explain the pro-hypertensive actions of stress in some of the population if we hypothesize that they have a GM dysbiosis that inhibits the breakdown of cortisol by 11HSD2.…”

Baroreceptors in the Aortic Arch and Their Potential Role in Aortic Dissection and Aneurysms

“…ENaCs are members of the amiloride-sensitive degenerin channel (DEG) family [ 7 , 8 , 9 , 10 , 11 , 41 , 43 ]. Four subunits (α, β, γ, and δ) have been detected thus far and are expressed in different tissues [ 11 , 12 , 13 , 14 , 15 , 16 ]. ENaCs play a significant role in the regulation of water homeostasis and as an Na+ transporter [ 17 ].…”

“…I, Intima, the inner aortic wall layer containing endothelial cells; M, Media, the middle aortic layer containing particularly smooth muscle cells, regulating the vascular tone; A, Adventitia, the outer aortic layer containing the mechanosensory baroreceptors. ENaCs, Epithelial sodium channels, containing four subunits (α, β, γ, and δ) [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]; ASICs, Acid-sensing ion channels [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ] belonging to the DEG/ENaC superfamily with at least seven ASIC isoforms; K+, Stretch-sensitive K+ channels, both calcium (Ca)-insensitive and Ca-sensitive [ 25 , 26 ]; TRP, transient receptor potential ion channels [ 6 , 27 , 28 , 29 , 30 , 31 ]: TRPA (ankyrin 1), TRPC (canonical 1–7), TRPM (melastatin 1–8), TRPN (NOMPC-like 1), TRPP (polycystin 2, 3, 5), TRPML (mucolipin 1–3), and TRPV (vanilloid 1–6): TRPV1, TRPC1, and TRPC3-7; PIEZO1, 2, mechanosensitive ion channels [ 32 , 33 , 34 ].…”