This thesis addresses the expression, regulation, and functional aspects of NOS in normal and developing skeletal muscles, and their role in contractile dysfunction of respiratory muscles associated with septic shock. Normal skeletal muscles of mammalian species express only ecNOS and nNOS to varying degrees. NOS activity in these muscles is mainly Ca2+/calmodulin-dependent and it associates with fast-twitch muscle fibers in rat and mice, but no such correlation exists in other species. Therefore, NOS activity is not the only factor that specifies contractility of skeletal muscles. In developing skeletal muscles, there is a transient increase in NOS Ca2+-dependent activity and the expressions of cNOS isoforms are upregulated. This coincides with skeletal muscle differentiation and maturation. Despite the negative influence of NOS activity on skeletal muscle contractility, little inhibition is observed on force generated by the developing diaphragm. Therefore, NO may regulate other processes than contraction in developing skeletal muscles. The in-vivo induction of iNOS protein and mRNA in skeletal muscles of septic rat is matched by a parallel induction in GTP-cyclohydrolase-I, the rate-limiting enzyme for BH4 biosynthesis. NOS Ca2+ -independent activity increases several fold mainly in the respiratory muscles. In addition, the expressions of cNOS enzymes are upregulated in septic rat muscles. During 24 hrs of endotoxemia of rats, iNOS is induced by 6 hrs, peak by 12 hrs and disappear by 24 hrs after LPS injection. nNOS and ecNOS expression is upregulated by 6 hrs and remained higher than control values after 24 hrs of LPS injection. The regulation of NOS isoforms is matched by an increase in total and Ca2+/calmodulin-independent NOS activity. Furthermore, peroxynitrite was detected in septic respiratory muscles, and nitrated proteins were detected in these muscles 12 hrs after LPS injection. Submaximal force generated by diaphragm strips was significantly inhibit
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.35499 |
| Date | January 1998 |
| Creators | El-Dwairi, Qasim. |
| Contributors | Hussain, S. N. A. (advisor), Magder, S. (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 Anatomy and Cell Biology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001650665, proquestno: NQ50292, Theses scanned by UMI/ProQuest. |
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