Studies of sarcoplasmic reticulum function in rabbit and human left ventricular dysfunction

Neary, Paul (1999) Studies of sarcoplasmic reticulum function in rabbit and human left ventricular dysfunction. PhD thesis, University of Glasgow.

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Heart Failure is a common clinical problem with high morbidity and mortality. While there are several pathological changes in cardiac failure, abnormalities of myocardial contraction at the cellular level are well documented. Myocyte Ca2+ handling which underlies excitation-contraction coupling is abnormal in heart failure and contributes to mechanical dysfunction. Changes in intracellular Ca2+ during contraction and relaxation are mediated by both sarcolemmal Ca2+ transport and sarcoplasmic reticulum (SR) Ca2+ release and re-uptake. Abnormalities of both sarcolemmal Ca2+ transport, and SR function have been described in heart failure and thus the pathophysiological mechanisms of abnormal handling and subsequent myocardial contraction need to be clarified. In this thesis, abnormalities of Ca2+ handling at the level of the whole myocyte are characterised in a coronary artery ligation model of heart failure in rabbit. Following this, a novel preparation for the specific study of SR function in permeabilised single, myocytes was developed. SR Ca2+ content was significantly reduced in myocytes from failing hearts compared to shams. Spontaneous SR Ca2+ release occurred less frequently in failure myocytes and with reduced amplitude than in myocytes from sham hearts. SR Ca2+ uptake was then directly measured in suspensions of single, permeabilised myocytes from failing rabbit hearts. SERCA 2A mediated SR Ca2+ uptake was significantly slower in failure cells than sham cells, and this difference was maintained in the presence of ruthenium red, a blocker of the SR Ca2+ release channel. Inhibitors of specific aspects of SR function were then used to model the changes in SR function seen in heart failure. Inhibition of SR Ca2+ uptake with thapsigargin in healthy permeabilised myocytes most closely modelled the heart failure phenotype. Inhibition of SR Ca2+ release at the ryanodine receptor with tetracaine, and stimulation of SR Ca2+ leak with ionomycin did not accurately model the changes in SR function seen in heart failure. The experimental techniques described in this thesis were then applied to human myocytes dissociated from small ventricular biopsies to ascertain whether similar protocols could be used in future studies to investigate SR function in human heart failure.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QP Physiology
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Smith, Professor Godfrey
Date of Award: 1999
Depositing User: Enlighten Team
Unique ID: glathesis:1999-71792
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 17 May 2019 09:31
Last Modified: 24 Oct 2022 11:04
Thesis DOI: 10.5525/gla.thesis.71792

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