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Title: The effect of modulating calcium-induced calcium release on the properties of spontaneous and systolic calcium release in rat ventricular myocytes.
Author: Overend, Catherine Louise.
ISNI:       0000 0001 3461 2484
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 1999
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The effects of modulation of CICR on spontaneous and systolic Ca2+ release were investigated in isolated rat ventricular myocytes. Spontaneous waves of Ca2 + release were initially abolished and then resumed at a lower frequency during exposure to 100 J.LMtetracaine. Both the duration of the initial quiescent period and oscillation frequency in tetracaine were dependent on the control oscillation frequency and the concentration of tetracaine applied. Electrophysiological quantification of the SR Ca2+ content of myocytes revealed a significant increase during exposure to tetracaine. The amplitude of spontaneous Ca2 + release was also increased such that despite decreased frequency, efflux per unit time activated by Ca2+ waves was not changed significantly. Using confocal microscopy, the spatial and temporal properties of Ca2+ waves were studied revealing that tetracaine inhibits the propagation of Ca2 + release. The increased SR Ca2+ content and the increased amplitude of Ca2+ release can reverse this effect. Application of 100 J.LMtetracaine to electrically stimulated cells transiently depressed systolic Ca2+ release and contraction but had no effect in the steady state. Removal of tetracaine was associated with potentiation of systolic Ca2+ release followed by gradual recove~. Quantification of the SR Ca2+ content revealed that in tetracaine the SR Ca + content was significantly increased in the steady state. This increase was accounted for by inhibition of systolic Ca2+ release activating less Ca2+ efflux in the presence of the same or increased Ca2+ influx on the L-type Ca2+ current. As the SR Ca2+ content increases, more efflux is activated until eventually efflux and influx balance in the steady state. The transient potentiation of contraction on removal of tetracaine is due to the increased SR Ca2 + content, which increases the gain of CICR in the absence of inhibition of Ca2 + release. The mechanism of post rest potentiation in rat cardiac tissue has not been conclusively elucidated by previous studies. This investigation provides evidence that changes in SR Ca2 + content and recovery of channels from inactivation could contribute to the potentiation of contraction observed in rat ventricle after a period of rest. Tetracaine enhances the degree of potentiation of contraction, which can only partially be attributed to its ability to enhance SR Ca2+ accumulation. During myocardial ischaemia dramatic changes in the substrate and metabolite levels in cells occur and a number of these changes are known to affect the RyR. However, the overall effects of metabolic blockade on the sensitivity CICR in intact cells have been overlooked. Experiments were carried out to investigate the effect of metabolic inhibition on spontaneous Ca2+ release and SR Ca2+ content in isolated rat ventricular myocytes. The results show that CICR is inhibited during metabolic inhibition. This could contribute to the degree of damaging and potentially fatal Ca2+ overload experienced on reperfusion of ischaemic tissue.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pharmacological modulators