The sarcoplasmic reticulum is the intramuscular organelle responsible for the regulation of cytoplasmic calcium levels in muscle. This thesis investigates the effects of the cardioprotective drug, dexrazoxane, and its metabolite ADR-925 on doxorubicin induced calcium release from skeletal sarcoplasmic reticulum. Doxorubicin is a widely used antineoplastic agent. One of the major side effects of doxorubicin usage is chronic cardiotoxicity. Doxorubicin is a potent activator of the calcium release mechanism from the SR. The interaction between doxorubicin and the calcium release channel has been proposed as the possible underlying mechanism behind cardiotoxicity. A short overview of different hypotheses describing doxorubicin induced cardiotoxicity and proposed mechanisms of cardioprotection by dexrazoxane are presented. While dexrazoxane did not appear to affect the calcium permeability of the SR, its metabolite, ADR-925, modulates the ryanodine receptor complex. ADR-925 inhibits high affinity ryanodine binding to the ryanodine receptor/calcium release channel complex by decreasing the sensitivity of the receptor for stimulation by calcium. ADR-925's ability to inhibit doxorubicin stimulated ryanodine binding is independent of the doxorubicin concentration. These results demonstrate that ADR-925 directly affects the ryanodine receptor complex of the SR by desensitizing the receptor to activation by calcium. Furthermore, ADR-925 reduces the inhibitory effect of hydrogen peroxide on the ryanodine receptor/ calcium release channel. This suggests that ADR-925 may protect the SR from oxidative effects of free radicals. It has been somewhat controversial whether doxorubicin induced cardiotoxicity is due to a specific interaction with the calcium release mechanism of SR. The findings presented in this thesis which demonstrate that the cardioprotectant ADR-925 interacts directly with the ryanodine receptor from SR, further support the hypothesis that the ryanodine receptor is a primary target of doxorubicin's action.
| Identifer | oai:union.ndltd.org:pdx.edu/oai:pdxscholar.library.pdx.edu:open_access_etds-6141 |
| Date | 08 November 1996 |
| Creators | Herzinger, Thomas Andreas |
| Publisher | PDXScholar |
| Source Sets | Portland State University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Dissertations and Theses |
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