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dc.contributor.advisorLamberts, Regis
dc.contributor.advisorErickson, Jeff
dc.contributor.authorSmeeton, Jack
dc.date.available2019-12-06T00:17:53Z
dc.date.copyright2019
dc.identifier.citationSmeeton, J. (2019). The forgotten arm of the fight-flight response: α-adrenergic control of the diabetic heart and interactions with Calmodulin Kinase 2 (Thesis, Bachelor of Medical Science with Honours). University of Otago. Retrieved from http://hdl.handle.net/10523/9830en
dc.identifier.urihttp://hdl.handle.net/10523/9830
dc.description.abstractIn Type 2 Diabetes Mellitus (T2DM) chronic metabolic stress and associated hemodynamic dysregulation result in a two-fold increase in cardiovascular disease (CVD) risk, making CVD a leading cause of death for T2DM patients (Sarwar et al., 2010). Furthermore, T2DM patients are at greater risk of surgical complications and require greater doses of catecholamines to avoid anaesthesia-induced hypotension during surgery (Bussey et al., 2014; Amour et al., 2004). In T2DM patients several alterations have been observed in adrenergic signalling of the heart, homeostatically important for regulation of cardiac function and involved in post-infarction and congestive heart failure outcomes (Madamanchi, 2007). α-Adrenergic Receptors (αARs), well known for regulating vascular function, have however not been explored to the same extent as β-AR signalling pathways for T2DM cardiac dysfunction. This project aimed firstly to determine the difference, and potential cross-talk, between αAR and β-AR stimulation in T2DM cardiac function. To this end, I used isolated Langendorff-perfused hearts from non-diabetics (NDM) and diabetics (DM) from Zucker Diabetic Fatty (ZDF) rats. The effect of different adrenergic drugs on left ventricular (LV) inotropy, lusitropy and chronotropy was tested. We found evidence for adrenergic cross-talk in lusitropic and inotropic parameters for NDM, but relied heavily on previous data for DM changes for our conclusions. Furthermore, in heart rate (HR) we found evidence we believe dissociates α-ARs from β-AR, with inverse responses seen between NDM and DM heart chronotropy. The second arm aimed to determine the effect of Calmodulin Kinase II (CaMKII) inhibition on the response to a physiological adrenergic agonist (Norepinephrine (NE), α1-AR and β-AR ii stimulation). This was again be tested at organ level by using isolated Langendorff perfused rat hearts from NDM and DM rats of our ZDF colony. In general, the results showed that the adrenergic inotropic and lusitropy response were dampened by CaMKII in NDM hearts, whilst diabetic hearts were unresponsive to CaMKII in broad β-AR stimulation. Furthermore, CaMKII may be responsible, in part, for the switch in adrenergic responsiveness for cardiac parameters in T2DM. In conclusion, the data in this project provides evidence that alterations in α1-AR activity in the DM hearts is likely dependent on a CaMKII mechanism by altering the β1-AR mediated inotropic and lusitropic response. Importantly, both independently, the α1-AR action and the β1-AR mediated modulation were reversed in the DM hearts. This highlights an important switching component of diabetic cardiac pathogenesis, thought to be related to CaMKII activity.
dc.language.isoen
dc.publisherUniversity of Otago
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dc.subjectAdrenergic
dc.subjectDiabetes
dc.subjectType 2 Diabetes Mellitus
dc.subjectCardiac
dc.subjectHeart
dc.subjectAlpha-Adrenergic Receptor
dc.subjectCAMKII
dc.subjectCalmodulin Kinase II
dc.subjectcatecholamine
dc.subjectnorepinephrine
dc.subjectLangendorff
dc.subjectZucker Diabetic Fatty Rats
dc.titleThe forgotten arm of the fight-flight response: α-adrenergic control of the diabetic heart and interactions with Calmodulin Kinase 2
dc.typeThesis
dc.date.updated2019-12-05T22:49:23Z
dc.language.rfc3066en
thesis.degree.disciplineDepartment of Physiology, Otago School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
thesis.degree.nameBachelor of Medical Science with Honours
thesis.degree.grantorUniversity of Otago
thesis.degree.levelHonours
otago.interloanno
otago.openaccessAbstract Only
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