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dc.contributor.advisorErickson, Jeff
dc.contributor.authorVeitch, Christopher Richard
dc.date.available2019-11-13T00:56:49Z
dc.date.copyright2019
dc.identifier.citationVeitch, C. R. (2019). The α-Adrenergic System and CaMKII in Diabetic Heart Disease (Thesis, Bachelor of Biomedical Sciences with Honours). University of Otago. Retrieved from http://hdl.handle.net/10523/9803en
dc.identifier.urihttp://hdl.handle.net/10523/9803
dc.description.abstractThe relationship between diabetes mellitus and heart disease is widely documented, with heart disease being the main cause of mortality in diabetic patients. Diabetes impairs the autonomic nervous system, leading to an imbalance between parasympathetic and sympathetic nervous output. Alterations in autonomic cardiac balance in diabetes may lead to fatal arrhythmias and impairments in contractility. Calcium/calmodulin-dependent protein kinase II (CaMKII) is a key regulator of cardiac contractility and is overactive in diabetes mellitus. CaMKII inhibition in diabetic models reduces both arrhythmogenic events and impaired cardiac contractility. Our laboratory has previously implicated CaMKII in the α-adrenergic cascade, although the role of both in diabetes-induced cardiac dysfunction is unclear. I hypothesised that CaMKII and the α-adrenergic system are dysregulated in diabetes, which may underlie arrhythmogenesis and impaired contractility in diabetic patients. Trabeculae from human right atrial appendage tissue were superfused with either methoxamine (an α-adrenergic agonist) or KN93 (a CaMKII inhibitor) followed by the two in conjunction. Changes in contractility and spontaneous contractions in the atrial samples were measured. CaMKII inhibition with KN93 consistently reduced the contractile function of the non-diabetic trabeculae and prevented a positive inotropic effect from methoxamine administration. This was consistent with previous work implicating CaMKII in the α-adrenergic cascade in mouse models. All samples showed no increase in arrhythmic events with methoxamine administration. We did not observe significant differences in the contractile response of diabetic and non-diabetic tissue with methoxamine administration. Diabetic tissue responded with an increase in developed force with addition of methoxamine and KN93, as opposed to non-diabetic tissue which showed a decrease in developed force. An equal proportion of both diabetic and non-diabetic samples showed a significant negative inotropic effect in response to methoxamine when compared with positive responders to the drug. The inotropic response to methoxamine seems to correlate with the duration of diabetes in diabetic patients, although some other factor may be influencing the non-diabetic negative inotropic response. This study is the first to implicate CaMKII in the α-adrenergic cascade in human cardiac tissue. The response to α-adrenergic stimulation seems to be dependent on a factor independent to diabetes, as similar proportions of negative responders to the drug were present in both non-diabetic and diabetic populations. The correlation of the blunted inotropic response to methoxamine with diabetes duration may be impacted by progressive denervation occurring in late stage diabetics, resulting in impaired responses to α-adrenergic agonists. The implication of CaMKII in the α-adrenergic cascade contraindicates the use of α-adrenergic agonists in conditions where overactive CaMKII may be pathological, such as diabetes.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectDiabetes
dc.subjectCaMKII
dc.subjectHeart
dc.subjectDiabetic Heart Disease
dc.subjectAlpha-adrenergic
dc.subjectContractility
dc.subjectCardiac
dc.subjectTrabeculae
dc.subjectHuman tissue
dc.subjectAtrial
dc.titleThe α-Adrenergic System and CaMKII in Diabetic Heart Disease
dc.typeThesis
dc.date.updated2019-11-13T00:41:31Z
dc.language.rfc3066en
thesis.degree.disciplinePhysiology
thesis.degree.nameBachelor of Biomedical Sciences with Honours
thesis.degree.grantorUniversity of Otago
thesis.degree.levelHonours
otago.openaccessOpen
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