Brief episodes of ischemia followed by reperfusion render the heart more resistant to injury from a subsequent prolonged ischemia. This endogenous and highly protective phenomenon is known as ischemic preconditioning. Although the phenomenon has been demonstrated virtually in all species tested including nun, the mechanism of ischemic preconditioning is incompletely understood. Early studies showed that both adenosine A1 receptors and K ATP channels appeared to mediate the effects of preconditioning in most species, but not in the rat. Therefore, we first investigated the signal transduction mechanisms involved in ischemic preconditioning against post-ischemic contractile dysfunction in isolated Langendorff-perfused rat hearts. We found that ischemic preconditioning in the rat heart is due to stimulation of alpha1B-adrenoceptors by release of endogenous catecholamines, resulting in acfivation of a pertussis toxin-sensitive guanine nucleotide binding (G) protein which enhances protein kinase C (PKC) activity. The results support the hypothesis that G protein-dependent PKC activation may be the common mechanism in signal transduction pathways of ischemic preconditioning among species. Accumulating evidence suggests that ATP-sensitive K+ channel (KATP channel) activation plays an important protective role in ischemic preconditioning. We hypothesized that PKC stimulation in ischemic preconditioning may produce cardioprotection by modulating KATP channel function, and studied further the modulation of the KATP channel by PKC-mediated phosphorylation, in rabbit and human ventricular myocytes, using voltage clamp techniques. We found that PKC activation stimulates KATP-induced opening at reduced intracellular ATP concentrations by reducing KATP channel sensitivity to intracellular ATP. In order to determine whether membrane-bound PKC could explain previously-described adenosine-induced KATP channel activation in excised membrane patches, we studied KATP channel function
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.34736 |
| Date | January 1997 |
| Creators | Hu, Keli. |
| Contributors | Nattel, Stanley (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pharmacology & Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001601616, proquestno: NQ44456, Theses scanned by UMI/ProQuest. |
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