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dc.contributor.authorSimpson, Nick
dc.contributor.otherQueen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.))en
dc.date.accessioned2018-07-31T17:55:27Z
dc.date.available2018-07-31T17:55:27Z
dc.identifier.urihttp://hdl.handle.net/1974/24416
dc.description.abstractCardiovascular disease is a leading cause of mortality worldwide. Progress has been made in diagnosing and treating this condition, however the mechanisms by which it develops have yet to be fully elucidated. Accumulating evidence suggests that inflammation plays an important role in cardiovascular disease. Cytokines are elevated in patients with hypertension and heart failure, as well as in animal models of these conditions. Tumor necrosis factor alpha (TNFα), a cytokine, has been shown to increase blood pressure and sympathetic output, and it is critical in the development of hypertension. It has been determined that the subfornical organ (SFO) of the central nervous system mediates the effects of TNFα. Knockdown of the TNFα receptor in the SFO ameliorates sympathoexcitation following heart failure, further suggesting a mechanism by which TNFα acts in the SFO to regulate cardiovascular function. However, it is unknown how TNFα modulates SFO neurons to cause these effects. Therefore, we performed whole-cell patch-clamp electrophysiology and [Ca2+]i imaging on dissociated SFO neurons isolated from male Sprague-Dawley rats to determine their activity in response to TNFα. We found that acute application of TNFα depolarized 50% of SFO neurons and increased their firing rate. We also found that chronic treatment of SFO neurons with TNFα increased their excitability, an effect that was mediated, at least in part, by a hyperpolarizing shift in the activation threshold of the voltage-gated Na+ current. Furthermore, we observed that TNFα potentiated angiotensin II-induced increases in [Ca2+]i in SFO neurons. This effect was also mediated by the voltage-gated Na+ current, as tetrodotoxin prevented this potentiation. These data suggest cellular mechanisms by which TNFα increases blood pressure and sympathetic activity through actions in the SFO, and thus provide new insight into how circulating inflammatory cytokines may contribute to cardiovascular regulation in health and disease.en_US
dc.language.isoenen_US
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjecttumor necrosis factor aphaen_US
dc.subjectsubfornical organen_US
dc.subjectangiotensin IIen_US
dc.subjectneuronen_US
dc.subjectcalciumen_US
dc.titleTumor necrosis factor alpha influences the excitability of subfornical organ neurons and potentiates angiotensin II-induced calcium activityen_US
dc.typethesisen
dc.description.degreeMaster of Scienceen_US
dc.contributor.supervisorFerguson, Alastair V
dc.contributor.departmentNeuroscience Studiesen_US


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