Journal article
Proinflammatory cytokines upregulate sympathoexcitatory mechanisms in the subfornical organ of the rat
Hypertension (Dallas, Tex. 1979), Vol.65(5), pp.1126-1133
05/2015
DOI: 10.1161/HYPERTENSIONAHA.114.05112
PMCID: PMC4393369
PMID: 25776070
Abstract
Our previous work indicated that the subfornical organ (SFO) is an important brain sensor of blood-borne proinflammatory cytokines, mediating their central effects on autonomic and cardiovascular function. However, the mechanisms by which SFO mediates the central effects of circulating proinflammatory cytokines remain unclear. We hypothesized that proinflammatory cytokines act within the SFO to upregulate the expression of excitatory and inflammatory mediators that drive sympathetic nerve activity. In urethane-anesthetized Sprague-Dawley rats, direct microinjection of tumor necrosis factor (TNF)-α (25 ng) or interleukin (IL)-1β (25 ng) into SFO increased mean blood pressure, heart rate, and renal sympathetic nerve activity within 15 to 20 minutes, mimicking the response to systemically administered proinflammatory cytokines. Pretreatment of SFO with microinjections of the angiotensin II type-1 receptor blocker losartan (1 μg), angiotensin-converting enzyme inhibitor captopril (1 μg) or cyclooxygenase-2 inhibitor NS-398 (2 μg) attenuated those responses. Four hours after the SFO microinjection of TNF-α (25 ng) or IL-1β (25 ng), mRNA for angiotensin-converting enzyme, angiotensin II type-1 receptor, TNF-α and the p55 TNF-α receptor, IL-1β and the IL-1R receptor, and cyclooxygenase-2 had increased in SFO, and mRNA for angiotensin-converting enzyme, angiotensin II type-1 receptor, and cyclooxygenase-2 had increased downstream in the hypothalamic paraventricular nucleus. Confocal immunofluorescent images revealed that immunoreactivity for the p55 TNF-α receptor and the IL-1 receptor accessory protein, a subunit of the IL-1 receptor, colocalized with angiotensin-converting enzyme, angiotensin II type-1 receptor-like, cyclooxygenase-2, and prostaglandin E2 EP3 receptor immunoreactivity in SFO neurons. These data suggest that proinflammatory cytokines act within the SFO to upregulate the expression of inflammatory and excitatory mediators that drive sympathetic excitation.
Details
- Title: Subtitle
- Proinflammatory cytokines upregulate sympathoexcitatory mechanisms in the subfornical organ of the rat
- Creators
- Shun-Guang Wei - From the Department of Internal Medicine, University of Iowa Carver College of Medicine (S.-G.W., Y.Y., Z.-H.Z., R.B.F.) and Veterans Affairs Medical Center (R.B.F.), Iowa City, IAYang Yu - From the Department of Internal Medicine, University of Iowa Carver College of Medicine (S.-G.W., Y.Y., Z.-H.Z., R.B.F.) and Veterans Affairs Medical Center (R.B.F.), Iowa City, IAZhi-Hua Zhang - From the Department of Internal Medicine, University of Iowa Carver College of Medicine (S.-G.W., Y.Y., Z.-H.Z., R.B.F.) and Veterans Affairs Medical Center (R.B.F.), Iowa City, IARobert B Felder - From the Department of Internal Medicine, University of Iowa Carver College of Medicine (S.-G.W., Y.Y., Z.-H.Z., R.B.F.) and Veterans Affairs Medical Center (R.B.F.), Iowa City, IA. robert-felder@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Hypertension (Dallas, Tex. 1979), Vol.65(5), pp.1126-1133
- Publisher
- United States
- DOI
- 10.1161/HYPERTENSIONAHA.114.05112
- PMID
- 25776070
- PMCID
- PMC4393369
- ISSN
- 0194-911X
- eISSN
- 1524-4563
- Grant note
- R01 HL096671 / NHLBI NIH HHS R01 HL073986 / NHLBI NIH HHS
- Language
- English
- Date published
- 05/2015
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984065491202771
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