Cardiac Sarcoplasmic Reticulum Function in Heart Failure

Denvir, Martin (1994) Cardiac Sarcoplasmic Reticulum Function in Heart Failure. PhD thesis, University of Glasgow.

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Heart failure is characterised by abnormalities of myocardial systolic and diastolic function. While there are changes in the structure of the heart which could account, in part, for these abnormalities, there is strong evidence to suggest that the regulation of calcium within the failing cardiac myocyte is abnormal. A diminished ability to release and sequester calcium could give rise to such contractile abnormalities and so the sarcoplasmic reticulum (SR), as the main site for calcium uptake and release, is the major focus of study in this thesis. Two rabbit models of heart failure were studied: adriamycin-induced cardiomyopathy and coronary artery ligation. The adriamycin-treated animals were studied 2 weeks after stopping 8 weeks of chronic intravenous administration. The coronary ligation animals were studied in two groups : 8 weeks after ligation and 15 weeks after ligation. The effects of down- regulation of adrenoreceptors on SR function was studied in a rabbit model following 7 days continuous administration of isoprenaline by mini-osmotic pump. Lastly, human ventricular trabeculae were studied from patients undergoing cardiac transplantation and are presented as a separate chapter. The severity of heart failure was assessed in each rabbit by echocardiography and by invasive measurement of cardiac output and left ventricular pressures. The preparation chosen to study the SR was the saponin-treated cardiac ventricular trabecula. This preparation has a number of advantages in that it leaves the SR anatomically undisrupted, the SR can load and leak calcium in a physiological way, the permeabilised sarcolemma allows free access to drugs and chemicals and the myofilaments may be assessed both in association with the SR and independently following treatment with the detergent Triton-X100. Furthermore, in our hands, this technique is very reliable and reproducible which is extremely important since very few animals which started the protocol, for any of the models, failed to produce results from the saponin-treated fibres. This has important implications for animal suffering. Sarcoplasmic reticulum function was assessed in the rabbit model of adriamycin-induced cardiomyopathy. The method for inducing cardiomyopathy is described in chapter 2 (methods 1) and the results are described in chapter 3. Unfortunately few animals with significant left ventricular dysfunction were produced but those with ejection fractions of less than 45% demonstrated enhanced SR Calcium loading compared with saline-treated controls and with adriamycin treated animals with higher ejection fractions. The ability of the myofilaments to produce force was unaffected by chronic treatment with adriamycin and the calcium responsiveness of the myofilaments was also unaffected by adriamycin treatment. 8 weeks after coronary ligation, rabbits with significant left ventricular dysfunction demonstrated enhanced SR calcium uptake compared with controls. A group of ligation animals with less severe left ventricular dysfunction, assessed by a scoring system, also demonstrated enhanced SR calcium loading but the difference between this group and sham-operated controls was less marked. Additionally , this enhanced SR calcium loading was correlated with a number of indices of heart failure including ejection fraction, left ventricular end-diastolic pressure and resting cardiac output. Enhanced SR calcium loading was associated with an increased predisposition to calcium overload, revealed as spontaneous tension oscillations. These oscillations were observed more frequently in the ligated animals and at lower loading calcium concentrations than in the control animals. This pattern of SR loading was observed in both left and right ventricular preparations although the greatest increase in SR loading was observed in the left ventricle. The ability of the myofilaments to produce force was not altered in the left ventricle but there was a fall in the maximum force produced by trabeculae from the right ventricle in the ligated group. The calcium responsiveness of the myofilaments was not different between groups. Chapter 4 examines SR calcium loading 15 weeks after coronary ligation. In these animals there was no significant difference in SR calcium loading ability between ligation and control trabeculae. The ligated animals demonstrated significant left ventricular dysfunction but this was not more severe than that observed in 8 week animals. Myofilament force production was unaltered as was calcium responsiveness of the myofilaments. Chapter 6 examines possible changes in the SR calcium release mechanism. There was no difference in the sensitivity of the mechanism of caffeine- induced calcium release in ligation animals compared with controls. Trabeculae from ligation animals appeared more sensitive to the calcium channel blocking agent, ryanodine, when applied during sustained oscillations. In a separate set of experiments SR calcium leak was assessed. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: S M Cobbe
Keywords: Physiology
Date of Award: 1994
Depositing User: Enlighten Team
Unique ID: glathesis:1994-74914
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 27 Sep 2019 15:13
Last Modified: 27 Sep 2019 15:13

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