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This dissertation, The Role of Ca2 in Protection of Preconditioning and Ischaemia-induced Injury in the Rat Heart by Wing-yi, Yan, 殷詠儀, 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: 2+ Abstract of the thesis entitled 'The Role of Ca in Protection of Preconditioning and Ischaemia-Induced Injury in the Rat Heart' submitted by Miss Wing Yi Yan for the Degree of Master of Philosophy at The University of Hong Kong in December, 2003 2+ 2+ There is evidence that an increase in cytosolic Ca ([Ca ]c) precedes 2+ myocardial injury during ischaemia, suggesting that [Ca ]c overload is a precipitating cause of myocardial injury. This suggestion was based on results obtained from correlative studies. On the other hand ischaemia preconditioning, 2+ which confers cardioprotection, induces a transient increase of [Ca ]c, which is believed to trigger the events that lead to cardioprotection against subsequent 2+ 2+ ischaemia insults. There is increasing evidence that mitochondrial Ca ([Ca ]m) may also be responsible for cardiac injury and protection. The purpose of the present study 2+ 2+ was to test the hypothesis that an increase in intracellular Ca ([Ca ]c and/or 2+ [Ca ]m) may be a precipitating cause of cardiac injury by a cause effect study. Secondly, the present study also attempted to test the hypothesis that a transient 2+ 2+ 2+ increase in intracellular Ca ([Ca ]c and/or [Ca ]m) may be responsible for 2+ cardioprotection of preconditioning. A cell permeable Ca chelator, BAPTA-AM was used. Both isolated myocyte and isolated perfused heart of rat were used. Two series iof experiments were conducted. Firstly, isolated ventricular myocytes were incubated with 2-deoxy-D-glucose (2-DOG) and sodium hydrosulphite (Na S O), which 2 2 4 produces metabolic inhibition and anoxia (MI/A), both consequences of ischaemia, for 10 mins followed by perfusion with normal Krebs solution (reperfusion) for 10 2+ 2+ mins. [Ca ]c and [Ca ]m were measured by spectroflurometry and confocal microscopy, respectively. It was found that 10-min ischaemia caused a significant 2+ 2+ increase in [Ca ]c, but not [Ca ]m, during ischaemia and reperfusion. The viability of the myocytes as determined by trypan blue exclusion was also decreased following ischaemia/reperfusion. BAPTA-AM at 1, 2.5 and 25 M significantly and 2+ dose-dependently attenuated the increase in [Ca ]c during ischaemia. At 2.5 and 25 M, BAPTA-AM also significantly and dose-dependently decreased the elevation 2+ of [Ca ]c during reperfusion and increased viability of the myocytes. To further 2+ determine whether the Ca chelator also reduce myocardial injury induced by ischaemia/reperfusion when administered in vivo, BAPTA-AM at 0.5-2.5mg/kg was injected intravenously into the rats. One hr later, the heart was isolated and perfused with normal Krebs solution for 30 mins and subjected to ischaemia by ligation of left coronary artery for 30 mins followed by release of the ligation that produced reperfusion for 2 hrs. Ischaemia/reperfusion (I/R) induced myocardial infarct. BAPTA-AM at 1mg/kg, 1.5mg/kg and 2.5mg/kg significantly reduced the infarct size, iiindicating a cardioprotective effect, which is in agreement with the observation in the myocyte preparation. The study, which was based on cause effect relationship, has 2+ provided unequivocal evidence that [Ca ]c overload during ischaemia is a precipitating cause of myocardial injury. In the second series of experiment, myocytes were subjected to 3 cycles of 3 mins of MI/A interspersed with 3 mins of reperfusion - preconditioning with MI/A. Then they were subjec

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