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A new pharmacological treatment for myocardial damage and arrhythmias arising from hypoxia, ischaemia or reperfusion

Weiss, Steven Michael

Description

Despite successful education campaigns through the media, and the evolution of numerous treatments, ischaemic heart disease remains one of the biggest causes of morbidity and mortality in the Western World. Development of anti-arrhythmic drugs was largely halted in the late'80s and early '90s prior to the discovery of the myocardial persistent sodium current and in particular, prior to the discovery that the myocardial persistent sodium current is considerably enhanced by hypoxia. We...[Show more]

dc.contributor.authorWeiss, Steven Michael
dc.date.accessioned2018-11-22T00:08:28Z
dc.date.available2018-11-22T00:08:28Z
dc.date.copyright2010
dc.identifier.otherb2569860
dc.identifier.urihttp://hdl.handle.net/1885/151555
dc.description.abstractDespite successful education campaigns through the media, and the evolution of numerous treatments, ischaemic heart disease remains one of the biggest causes of morbidity and mortality in the Western World. Development of anti-arrhythmic drugs was largely halted in the late'80s and early '90s prior to the discovery of the myocardial persistent sodium current and in particular, prior to the discovery that the myocardial persistent sodium current is considerably enhanced by hypoxia. We hypothesised that persistent sodium current blockade may reduce the extent of myocardial damage and the incidence of arrhythmias, and in particular lethal arrhythmias, arising from ischaemic heart disease. METHODS: Patch clamping and fluorescence studies were performed to determine whether Riluzole blocked persistent sodium currents and calcium influx during hypoxia and reperfusion. Isolated heart studies were performed to determine whether Riluzole provided cardioprotection during ischaemia-reperfusion. Whole animal studies were performed to determine whether Riluzole reduced the extent of myocardial damage and the incidence of arrhythmias from ischaemia and/or from ischaemia-reperfusion. Whole animal studies were also performed to determine whether Riluzole reduced the extent of skeletal muscle damage from ischaemia and/or reperfusion. RESULTS: Riluzole was found to: block persistent but not transient sodium currents, inhibit calcium influx and enhance cell shortening, enhance recovery from global ischaemia, not affect monophasic action potentials, reduce the extent of ischaemic myocardial damage, reduce the extent of reperfusion myocardial damage, halve the number of animals developing sustained arrhythmias, not alter the phases of arrhythmias, reduce the incidence of all types of ischaemic Phase 2 arrhythmias, reduce the incidence of all types ofreperfusion Phase 2 arrhythmias, be a more selective persistent sodium current blocker and better antiarrhythmic and anti-ischaemic than Lidocaine, not possess class 1 antiarrhythmic properties, be positively inotropic, be positively lusitropic, reduce the extent of ischaemic damage in skeletal muscle, reduce the extent of reperfusion damage in skeletal muscle, and most importantly, be safe for administration at doses similar to those used for treating Amyotrophic Lateral Sclerosis. CONCLUSIONS: Riluzole appears to be extremely potent for treating ischaemic heart disease and for providing cardioprotection in the current setting where there are no other satisfactory drugs. Riluzole also appears to have potential in treating skeletal muscle ischaemic and reperfusion.
dc.format.extentxxvi, 284 leaves.
dc.language.isoen_AU
dc.rightsAuthor retains copyright
dc.subject.lccRC683.8.W45 2010
dc.subject.lcshHeart Diseases Treatment
dc.subject.lcshIschemia
dc.subject.lcshArrhythmia
dc.titleA new pharmacological treatment for myocardial damage and arrhythmias arising from hypoxia, ischaemia or reperfusion
dc.typeThesis (PhD)
local.description.notesThesis (Ph.D.)--Australian National University
dc.date.issued2010
local.type.statusAccepted Version
local.contributor.affiliationAustralian National University
local.identifier.doi10.25911/5d515528b036c
dc.date.updated2018-11-21T10:47:59Z
dcterms.accessRightsOpen Access
local.mintdoimint
CollectionsOpen Access Theses

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