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Title: Endothelin system expression and function in failing and nonfailing myocardium
Author: Wallace, Alison Fiona
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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The aims of this thesis were to investigate the endothelin system in failing and nonfailing myocardium and to evaluate the role of ET receptor function in relation to contractility in vivo and in vitro. In addition, transmural differences in gene expression were explored in human failing myocardium to establish whether genes associated with stiffness, hypertrophy and the ET system correlate to wall stress. Rats underwent myocardial infarction (MI) and developed left ventricular (LV) dysfunction at 15 weeks post-MI, as evidenced by an increase in LV end-diastolic pressure (LVEDP, 3 ± 0.2mmHg to 12 ± 2mmHg, P<0.01) and an increase in expression of atrial natriuretic peptide mRNA. A reduction in the basal contractile response of papillary muscles from failing hearts was also consistent with dysfunction. However, responses to ET-1 were inconsistent and prevented conclusions about the role of individual receptors. Investigation of ET receptor expression by RT-PCR failed to show a selective increase in ETB receptors and prepro ET-1 mRNA remained unchanged at 15 weeks post-MI. Subsequently, experiments were designed to investigate the influence of ET on myocardial contractility using ET receptor antagonists in papillary muscles from control animals. Results suggested that both ET receptors contribute to contractility in rat myocardium, corresponding with the presence of both receptor subtypes, found using RT-PCR. Furthermore, the data showed that expression of ET receptors in the heart undergo seasonal variation, which corresponds with the contribution of receptors to regulation of contractility. LV function was evaluated in vivo using a novel technique developed in our laboratory. Echocardiography in conjunction with associated LV pressure data demonstrated a reduced shortening fraction (SF, 18.7 ± 1.9% to 13.6 ± 1.3%, P<0.05) and ejection fraction (EF, 31.1 ± 2.6% to 22.4 ± 1.2%, P<0.01) in rats 12 weeks post-MI indicating LV dysfunction, also evidenced by elevated LVEDP (5.7 ±1.0mmHg to 15.6 ±1.5mmHg P<0.001).  Subsequently, the technique was used on control animals following chronic (7 day) administration of Bosentan, a dual ET receptor antagonist (100mg/kg/day). However, antagonist treatment failed to influence haemodynamics, SF or EF, suggesting that unlike in vitro, the ET system does not play a central role in regulating cardiac function in vivo. In the human heart, wall stress is highest in the endocardial layer. Different types of heart failure alter myocardial contractility and wall stress in different ways. Semi-quantitative RT-PCR identified that genes linked to hypertrophic remodelling were consistently increased in the endo relative to epicardium. Interestingly, expression of the ETA receptor and the cytoskeletal elastic protein, titin, in particular the N2B isoform linked to increased myocardial stiffness showed 2 distinct patterns of expression across the LV wall, depending on the type of heart failure. ETB expression was uniform across the wall. In conclusion, the ET system is expressed in the normal myocardium and both receptors can regulate contractility in vitro, however the system is not essential for normal heart function in vivo.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available