title: 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.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; and kojiitoh@cardiol.med.kyushu-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Ito
authors.affiliation: Department of Advanced Cardiovascular Regulation and Therapeutics, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hirooka
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; and.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000200:Action Potentials; D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000294:innervation*; D007031:Hypothalamus / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009638:Norepinephrine / Q000652:urine; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D018689:Sensory System Agents / Q000494:pharmacology; D012964:Sodium / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D053503:Epithelial Sodium Channels; D018161:Receptors, Mineralocorticoid; D018689:Sensory System Agents; D026941:Sodium Channel Blockers; D014409:Tumor Necrosis Factor-alpha; C013407:benzamil; D000431:Ethanol; D000584:Amiloride; D012964:Sodium; D002211:Capsaicin; D009638:Norepinephrine
keywords: cardiac sympathetic afferent reflex; heart failure; heart-brain communication; hypothalamus; salt