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dc.contributor.authorLouch, William Edward.en_US
dc.date.accessioned2014-10-21T12:33:48Z
dc.date.available2014-10-21T12:33:48Z
dc.date.issued2001en_US
dc.identifier.otherAAINQ67653en_US
dc.identifier.urihttp://hdl.handle.net/10222/55827
dc.descriptionExposure to ischemia and reperfusion can trigger protracted contractile depression in the myocardium, despite normal electrical activity and the absence of irreversible damage. This condition is known as myocardial stunning. Although it is believed that stunning is associated with reduced responsiveness of the myofilaments to Ca2+, it is unclear whether altered Ca2+ homeostasis in late reperfusion also might contribute to this condition. This question was addressed by examining EC coupling in an isolated myocyte model of stunning. The cellular model was developed by demonstrating that isolated myocytes exposed to 30 min of simulated ischemia exhibited contractile depression in reperfusion that was not associated with alterations in action potential configuration. Stunned myocytes exhibited normal Ca2+ transients, supporting the view that reductions in myofilaments responsiveness are a key component of the physiology of stunning. Stunned myocytes also exhibited normal diastolic [Ca2+] i and SR Ca2+ content, but ICa-L was reduced. Contractions elicited by the VSRM and CICR were similarly depressed in late reperfusion, suggesting that the gain of CICR may be increased in stunning. Increased Ca2+ influx, possibly by the NaCaex may compensate for post-ischemic reductions in ICa-L to maintain a normal Ca2+ transient in reperfusion. The results support the view that altered Ca2+ homeostasis could contribute to contractile depression in stunning. In a second series of experiments, the actions of the AT1 receptor antagonist, losartan, were examined in the cellular model of stunning. Losartan treatment during ischemia protected against stunning by a mechanism that appeared to be independent of AT1 blockade. Since losartan also inhibited ITI in early reperfusion, it was hypothesized that losartan may protect against Ca2+ overload. Losartan was, in fact, observed to attenuate increases in diastolic [Ca 2+]i during ischemia and prevent overshoot of Ca 2+ transients in early reperfusion. Losartan also increased the magnitude of Ca2+ transients in late reperfusion. SR Ca2+ stores appeared to be increased in losartan-treated cells without effects on diastolic [Ca2+]i, an action that could explain the protective actions of losartan in ischemia and reperfusion. These results suggest that losartan may increase SR Ca2+ stores, possibly by increasing activity of the SR Ca2+ ATPase, by an action independent of AT1 blockade.en_US
dc.descriptionThesis (Ph.D.)--Dalhousie University (Canada), 2001.en_US
dc.languageengen_US
dc.publisherDalhousie Universityen_US
dc.publisheren_US
dc.subjectBiology, Cell.en_US
dc.subjectHealth Sciences, Pharmacology.en_US
dc.subjectBiology, Animal Physiology.en_US
dc.titleCardiac ischemia and reperfusion: Cellular physiology and pharmacological intervention.en_US
dc.typetexten_US
dc.contributor.degreePh.D.en_US
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