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This dissertation, Excitation Contraction Coupling of Ventricular Myocyte in Septic Shock: Role of a Change in Calcium Cycling System by Chun-hung, Barry, Lau, 劉俊雄, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Excitation Contraction Coupling of Ventricular Myocyte in Septic Shock - Role of a Change in Calcium Cycling System submitted by Lau Chun Hung Barry for the degree of Master of Philosophy at the University of Hong Kong in November, 2007 Every year in the United States alone, 200000 to 300,000 septic patients die from cardiovascular failure. It is a common death in intensive care units. Heart failure, due to the hypodynamic phase in septic shock, is believed to be the major killer. However, the intracellular mechanisms involved remains to be elucidated. Here, we have investigated deep down from the contractility of myocytes, to the molecular changes of regulatory proteins. In our studies, septic shock was induced in adult rats by the injection of lipopolysaccharide (LPS). In this disease model, ventricular action potential is shorter, the calcium signal and the associated twitch contraction are also smaller. As Sarcoplasmic Reticulum (SR) is generally agreed to be the major regulator of intracellular calcium, impairment of its ability to handle calcium could play an important role in our heart failure model. To reveal the secrets behind, experiments investigating the SR calcium content were conducted using freshly isolated ventricular myocytes. By measuring the graded contractures induced by caffeine, the deprived SR calcium is disclosed. In the LPS group, not only the rate, but also the amount of refilling of SR calcium content was reduced. This observation suggested a reduced uptake of calcium, perhaps due to a decreased phosphorylation of phospholaman (PLB). iii Western immunoblotting analysis of isolated SR vesicles showed no significant difference in the amount of total PLB, but the proportion of phosphorylated PLB was significantly smaller in the LPS group. This implies that inhibition to the pumping activity of sarcoplasmic reticulum ATPases (SERCA) is enhanced in our LPS model. This reduced SERCA activity contributes to the calcium mishandling of the SR and ultimately to the impaired twitch contraction. The calcium cycling system became maladaptive during septic shock due to down-regulation of PKA-dependent phosphorylation of PLB linked to increased Gi activity, probably as a consequence of a PKA-dependent phosphorylation of the ADM receptor requiring the presence of COX II. (Word Count: 314) iv DOI: 10.5353/th_b3955832 Subjects: Excitation (Physiology)Septic shockHeart cellsHeart - ContractionCalcium channelsCalcium - Physiology

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