Abstract
The purpose of this research is to clarify the role of catecholamines in ischaemia-induced ventricular fibrillation (VF) - a common lethal event and largely unmet therapeutic need, contributing greatly to the overall prevalence of sudden cardiac death (SCD). β blockers have been widely used in patients most at risk of SCD, i.e. with ischaemic heart disease or acute myocardial infarction, and have been successful in moderately reducing mortality rates. However, for reasons that are still unknown, VF and SCD are still prevalent in patients at risk, indicating that the benefits of β blockers are limited. In order to maximise the benefits of β blocker treatment, it is necessary to characterise the circumstances and precise extent to which catecholamines facilitate ischaemia-induced VF, and the mechanisms involved. The data from this research will then establish the factors determining whether adrenoceptor (AR) antagonism is beneficial for SCD suppression, potentially facilitating more precise targeting of patients for treatment.This project aims to test the hypothesis that when ischaemia alone is an insufficient trigger for VF (suboptimal ischaemia), because coronary obstruction is too low down the coronary tree (resulting in a small ischaemic zone [IZ]), catecholamines may be sufficient to tip the electrophysiological balance in favour of VF.
The small IZ model (Langendorff perfused rat hearts) was validated and specific conditions selected to achieve a low control incidence of VF (5%). The addition of catecholamines (75 nM adrenaline + 313 nM noradrenaline) significantly increased the incidence of VF to 40%. Receptor mechanisms of catecholamine facilitated VF were determined using selective antagonists (1 μM): atenolol (β1), butoxamine (β2) and trimazosin (α1). Atenolol and butoxamine but not trimazosin reduced VF. Western blot analysis of downstream β1 and β2 signalling proteins from these hearts confirmed that β1 and β2 ARs mediate the facilitation of ischaemia-induced VF by catecholamines.
Date of Award | 4 Jul 2016 |
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Original language | English |
Awarding Institution |
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Supervisor | Michael Curtis (Supervisor) |
Keywords
- Pharmacology & pharmacy & pharmaceutical chemistry
- heart
- cardiac arrhythmia