title: Subfornical organ mediates sympathetic and hemodynamic responses to blood-borne proinflammatory cytokines.
abstract: Proinflammatory cytokines play an important role in regulating autonomic and cardiovascular function in hypertension and heart failure. Peripherally administered proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), act on the brain to increase blood pressure, heart rate, and sympathetic nerve activity. These molecules are too large to penetrate the blood-brain barrier, and so the mechanisms by which they elicit these responses remain unknown. We tested the hypothesis that the subfornical organ (SFO), a forebrain circumventricular organ that lacks a blood-brain barrier, plays a major role in mediating the sympathetic and hemodynamic responses to circulating proinflammatory cytokines. Intracarotid artery injection of TNF-α (200 ng) or IL-1β (200 ng) dramatically increased mean blood pressure, heart rate, and renal sympathetic nerve activity in rats with sham lesions of the SFO (SFO-s). These excitatory responses to intracarotid artery TNF-α and IL-1β were significantly attenuated in SFO-lesioned (SFO-x) rats. Similarly, the increases in mean blood pressure, heart rate, and renal sympathetic nerve activity in response to intravenous injections of TNF-α (500 ng) or IL-1β (500 ng) in SFO-s rats were significantly reduced in the SFO-x rats. Immunofluorescent staining revealed a dense distribution of the p55 TNF-α receptor and the IL-1 receptor accessory protein, a subunit of the IL-1 receptor, in the SFO. These data suggest that SFO is a predominant site in the brain at which circulating proinflammatory cytokines act to elicit cardiovascular and sympathetic responses.
authors.affiliation: Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Shun-Guang
authors.initials: SG
authors.lastname: Wei
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Zhang
authors.forename: Terry G
authors.initials: TG
authors.lastname: Beltz
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Alan Kim
authors.initials: AK
authors.lastname: Johnson
authors.forename: Robert B
authors.initials: RB
authors.lastname: Felder
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects*; D017776:Autonomic Pathways / Q000187:drug effects / Q000502:physiology*; D001812:Blood-Brain Barrier; D016207:Cytokines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013356:Subfornical Organ / Q000187:drug effects / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*
chemical_list: D016207:Cytokines
keywords: cytokine receptors; proinflammatory cytokines; subfornical organ; sympathetic drive