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Download (4MB) https://theses.gla.ac.uk/ Theses Digitisation: https://www.gla.ac.uk/myglasgow/research/enlighten/theses/digitisation/ This is a digitised version of the original print thesis. Copyright and moral rights for this work are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This work cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Enlighten: Theses https://theses.gla.ac.uk/ [email protected] Natural and synthetic factors which influence the calcium sensitivity of chemically-skinned rat cardiac muscle A thesis submitted for the degree of Doctor of Philosophy © D. S. Steele 1990 Institute of Physiology, Glasgow University ProQuest Number: 11003372 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 11003372 Published by ProQuest LLC(2018). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 Contents Page number List of contents................................................................................................. (i-v) List of figures.................................................................................................. (vi-viii) List of tables................................................................................................... (ix) Abbreviations................................................................................................... (x) Acknowledgements........................................................................................ (xi) Summary............................................................................................................ (xii-xv) Chapter 1: General Introduction Excitation contraction coupling in striated muscle........................ 2 The regulation of force in striated muscle.......................................... 4 Changes in contractile force with length............................................. 4 Physical factors and the length-tension relationship...................... 5 Changes in activation with muscle length.......................................... 5 Endogenous modulators of Ca-sensitivity............................................ 6 Ca-sensitivity and the hydrolysis of A TP............................................ 7 Ionic strength................................................................................................... 7 a and /3-receptor stimulation................................................................... 8 Endogenous imidazoles............................................................................... 10 Taurine................................................................................................................ 10 Synthetic Ca-sensitisers................................................................................ 11 Mechanisms underlying changes in Ca-sensitivity. Length-dependent changes in Ca-sensitivity..................................... 12 Ionic strength and pH................................................................................. 14 Caffeine and related compounds........................................................... 15 Inorganic phosphate...................................................................................... 18 Conclusions....................................................................................................... 18 Chapter 2: Materials and Methods General protocol............................................................................................ 21 Preparation mounting and force measurement............................... The microscope system and measurement of ..............................s.l 22 Solution exchange.......................................................................................... 24 Chemical supplies.......................................................................................... 25 Solution Composition.................................................................................. 25 p H ........................................................................................................................ 26 Ionic strength................................................................................................... 28 Calculation of free metal concentrations.............................................. 28 The chemical skinning procedure......................................................... 29 Data Handling................................................................................................. 31 Data analysis.................................................................................................... 32 The Hill Equation......................................................................................... 33 Chapter 3 Caffeine contractures in saponin-skinned trabeculae Introduction Protocol for caffeine-induced contractures........................................ 36 Effects of caffeine on intact tissue........................................................ 37 Experiments on isolated s.r....................................................................... 39 Experiments on selectively-skinned cardiac muscle....................... 39 The effect of caffeine on isolated s.r. channels.............................. 40 The aim of this chapter............................................................................. 40 R esults Oscillations in saponin-skinned trabeculae........................................ 43 Caffeine and relaxations from submaximal activation................. 46 The effect of caffeine on the relaxation from Cmax.................... 46 Mitochondria and the caffeine contractures..................................... 47 D iscussion Oscillating and steady-state tension production....................... 49 The effect of caffeine on the rate of relaxation............................. 52 The relevance of these results to the current study..................... 54 ii Chapter 4: The effect of cAMP on skinned trabeculae. Introduction Catecholamines, cyclic nucleotides and contractility...................... 58 The effect of cAMP sarcolemmal channels...................................... 58 The effect of cAMP on the sarcoplasmic reticulum..................... 59 Cyclic nucleotides and the contractile proteins 59 Phosphodiesterase......................................................................................... 62 Saponin-treated trabeculae........................................................................ 64 The aim of this chapter.............................................................................. 65 R esults Adenylate cyclase and forskolin toxin................................................ 66 Exogenous cAMP and the caffeine contracture............................ 67 The variability of the phenomenon....................................................... 68 The effect of PDE inhibition on the cAMP response................. 69 cGMP on the caffeine contracture........................................................ 71 Cyclic nucleotides and Ca-sensitivity..................................................... 71 D iscussion Forskolin Toxin and the activity of adenylate cyclase.................. 74 cAMP and the caffeine contracture...................................................... 75 Phosphodiesterase and the caffeine response................................. 77 Cyclic nucleotides and Ca-sensitivity................................................... 78 Conclusions....................................................................................................... 81 Chapter 5: Caffeine and sulmazole: comparative aspects. Introduction Sulmazole and the contractile proteins............................................... 83 Effects on cardiac sarcoplasmic reticulum......................................... 84 The aim of this study.................................................................................. 84 R esults Protocol to determine s.r. Ca-release.................................................. 86 Caffeine, sulmazole and s.r. [Ca] release.......................................... 86 Accumulated data.......................................................................................... 87 Increased Ca-sensitivity and contracture amplitude...................... 88 Effect of caffeine and sulmazole on CICR oscillations............... 90 Effects on maximum Ca-activated force............................................. 90 iii D iscussion Effects on the sarcoplasmic reticulum................................................ 92 Effects on submaximal force production.......................................... 93 Effects on maximum Ca-activated force........................................... 94
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