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Investigation Of The Role Of The KATP Channel In Vascular Hyporeactivity In Sepsis

Buckley, James Francis; (2017) Investigation Of The Role Of The KATP Channel In Vascular Hyporeactivity In Sepsis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The lack of responsiveness of vascular smooth muscle cells (VSMCs) to vasopressor catecholamines is termed vascular hyporeactivity. Vascular hyporeactivity is an important component of sepsis. ATP-sensitive potassium channels (KATP) play a fundamental role in vascular hyporeactivity in long-term (>20hrs) sepsis. These channels remain in the open state, leading to membrane hyperpolarisation and subsequent relaxation of VSMCs. However, the precise mechanism of KATP activation in sepsis has yet to be elucidated. Disruption of the actin cytoskeleton, the direct effect of nitric oxide and the metabolic state of the cell all activate KATP channels and are possibilities. Therefore, three hypotheses were investigated: 1). Disruption of the actin cytoskeleton alters KATP channel function 2). Nitric oxide exerts a direct effect on the KATP channel. 3). Metabolic derangement is responsible for altered KATP channel function. Using confocal microscopy and biochemistry, it was demonstrated that the actin cytoskeleton of VSMCs was not disrupted in sepsis, and is therefore an unlikely mechanism for KATP channel activation. There was, however, a functional impairment of vascular function, indicating a lack of correlation between structure and function in the context of the model investigated. That NO has a direct effect on the KATP channel, and is subsequently responsible for its altered function in sepsis was also inconclusive. Finally, using HPLC techniques, no evidence to suggest that altered levels of adenosine nucleotide phosphates cause dysregulation of the KATP channel in either in vitro or in vivo models of sepsis (despite evidence of functional impairment) was observed. Therefore, in the context of the models used, none of the afore-mentioned mechanisms were shown to be responsible for the altered KATP channel observed in vascular tissue in sepsis.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigation Of The Role Of The KATP Channel In Vascular Hyporeactivity In Sepsis
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis from July 2012
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: http://discovery.ucl.ac.uk/id/eprint/10022695
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