Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555957
Title: Adrenaline-mediated biased agonism at the B2 adrenoceptor in an in vivo model of Takotsubo cardiomyopathy
Author: Paur, Helen Elizabeth
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Abstract:
Stress (Takotsubo) cardiomyopathy is a severe form of acute heart failure (HF) with rapid onset, characterized by hypocontraction of the heart from the mid-left ventricle to apex. It is precipitated by extreme stress and plasma levels of the catecholamines adrenaline and noradrenaline are significantly elevated. This thesis describes the development of a new model of Takotsubo cardiomyopathy through rapid intravenous injection of a supraphysiological dose of adrenaline into anaesthetised male Sprague- Dawley (SD) rats and real-time imaging of the heart using either 2D-echocardiography or cardiac magnetic resonance (CMR). This in vivo rat model was used, in conjunction with in vitro IonOptix video-edge detection of cardiomyocyte contractility, to firstly demonstrate that this syndrome results from an adrenaline-induced trafficking-switch of the coupling of the pleiotropic β2-adrenceptor (AR) from Gs-adenylyl cyclase (AC)-cyclic adenosine monophosphate (cAMP) cardiostimulant to Gi-activated cardiodepressant pathways. Cardiomyocyte β2AR:β1AR population ratios, determined by radioligand binding, suggested that an apical-basal gradient in β2AR expression accounted for the in vivo apical hypokinesis. Certain β-blockers can act as biased agonists of a Gi-coupled isoform of the β2AR in animal and human cardiomyocytes via a pathway that involves p38 MAPK. Administration of the clinical β-blockers propranolol and carvedilol 15 minutes after adrenaline either enhanced or failed to reverse apical hypocontractility. In vitro analysis demonstrated that β2AR-Gi signalling involves p38 MAPK activation. However, pre-treatment with either the p38 MAPK inhibitor SB203580 or the β2AR blocker ICI-118,551 prior to adrenaline resulted in significant mortality, which suggested that the β2AR-Gs/Gi coupling switch is a cardioprotective strategy. Gi-protein is upregulated in chronic HF, while β1ARs are down-regulated. In contractility studies of chronically failing human/rat cardiomyocytes, β2AR-Gs responses were present with minimal active Gi-protein component. This suggested that while in acute HF β2AR-Gs positively inotropic responses are impaired and β1ARs are preserved, the opposite may be true in chronic HF.
Supervisor: Lyon, Alexander ; Gorelik, Julia ; Harding, Sian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.555957  DOI: Not available
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