Browsing by Department "MRC/UCT Cape Heart Centre"

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    Arrhythmogenic potential of alpha-adrenoceptor stimulation in the rat heart
    (1985) Flint, Nigel Stuart; Thandroyen, Francis Trevor
    A recent proposal is that the alpha₁-adrenoceptor may mediate the arrhythmogenic effect of catecholamines during acute myocardial ischaernia. The purpose of this thesis was to explore the role of alpha₁ and alpha₂-adrenoceptor stimulation on vulnerability to ventricular fibrillation in the norrnoxic rat ventricular myocardium and further to evaluate the possible underlying cellular mechanism. The model used was the isolated perfused rat heart (Langendorff technique) in which ventricular fibrillation was electrically induced. The amount of current required to produce ventricular fibrillation was measured as the ventricular fibrillation threshold. Alpha₁-adrenoceptor stirnμlation with methoxamine to 10⁻⁶M to 10⁻⁵M increased the vulnerability to ventricular fibrillation. The arrhythmogenic effect of methoxamine could not be attributed to beta-adrenoceptor stimulation as it occurred in the setting of the beta-adrenoceptor antagonist agent, atenolol; furthermore no accumulation of cyclic AMP, the proposed arrhythmogenic second messenger of beta-adrenoceptor stimulation, occurred. Similarly no alteration in heart rate, coronary flow rate or myocardial high energy phosphate content accompanied the arrhythrnogenic effect of methoxamine. The QT interval increased with alpha₁-adrenoceptor stimulation, this being an indirect index of prolongation of the action potential duration. The arrhythmogenic action of methoxamine was associated with a positive inotropic effect. Prazosin 10⁻⁸M (an alpha₁-adrenoceptor antagonist agent) produced a tenfold displacement to the right of the log concentration response curve of the positive inotropic effect of methoxamine. Prazosin 10⁻⁸M prevented the methoxamine induced fall in ventricular fibrillation threshold. Alpha₂-adrenoceptor stimulation with B-HT 920 and B-HT 933 (azepexole), in the presence of the beta-adrenoceptor antagonist agent atenolol, did not alter the vulnerability to ventricular fibrillation. Alpha₂-adrenoceptor stimulation produced no alteration in heart rate, coronary flow rate or metabolic status. We next explored the possible mechanism underlying the arrhythmogenic effect of methoxamine. Alpha₁-adrenoceptor stimulation enhances transsarcolemmal calcium ion influx and may induce sarcoplasmic reticulum calcium release. To assess the role of transsarcolemmal calcium movement in alpha₁-adrenoceptor mediated effects experiments were undertaken with nisoldipine and low extracellular calcium. To evaluate the role of sarcoplasmic reticulum calcium release, experiments were undertaken with ryanodine (an agent reputed to inhibit sarcoplasmic reticulum calcium release without effecting the slow inward current). Nisoldipine 10⁻⁸M, reducing extracellular calcium (2.5 mM to 1.25 mM) and ryanodine 10⁻⁹M to 10⁻⁸M, prevented the arrhythmogenic and positive inotropic effect of methoxamine. Heart rate, metabolic status and cyclic AMP levels we're unchanged with these procedures. The mechanism underlying the arrhythmogenic action of alpha₁-adrenoceptor stimulation might be an increase in cytosolic calcium concentration. This increase may be secondary to (i) an enhanced transsarcolemmal calcium influx or (ii) an increase in the phasic release of calcium from the sarcoplasmic reticulum.
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    Electrophysiological mechanism of ventricular automaticity : a model foe ventricular arrythmias
    (1984) Saman, Selva; Saman, Selva; Opie, Lionel H
    Ventricular arrhythmias are difficult to study in man. The current experimental models are arrhythmias induced by electrical stimulation, coronary artery ligation or by subsequent reperfusion. An electrophysiological model will be useful for exploring the cellular mechanism of arrhythmias and for studying the mechanism of action of new anti-arrhythmic drugs. This project seeks to establish automaticity as a model for studying ventricular arrhythmias. Objectives 1. To review the literature on the mechanism of ventricular arrhythmias. 2. To explore ventricular automaticity induced by "reperfusion" after O₂ and substrate deprivation. 3 . To explore beta-adrenoceptor mediated ventricular automaticity. 4 . To evaluate possible new anti-arrhythmic drugs, carminomycin and ketanserin.
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    Fat as a fuel for exercise
    (2000) Goedecke, Julia
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    Metabolism in myocardial ischaemia and reperfusion with specific reference to the role of glucose
    (1996) King, Linda Mary; Opie, Lionel H
    Hypothesis: Glucose is known to be protective in moderate low flow ischaemia due to the production of glycolytic ATP. However, it is questioned whether glucose would still be protective in ultra-low flow ischaemia. Firstly, glycolysis is thought to be inhibited, and secondly, deleterious glycolytic metabolites accumulate. Our hypothesis was that in ultra-low flow ischaemia, glucose utilisation is not inhibited at the level of glycolysis, but by delivery. Increased delivery of glucose should result in increased production of protective glycolytic ATP, but the rate of metabolite accumulation would also increase. Using ultra low flow rates, I wished to investigate how to achieve optimal rates of glycolysis, and how such rates would be balanced by any detrimental component of metabolite accumulation. Methods: The isolated Langendorff-perfused rat heart, with a left ventricular balloon to record ischaemic contracture and reperfusion stunning, was used, with severe flow restriction. Glucose concentrations were changed and pre-ischaemic glycogen contents were altered by perfusion with different substrates (acetate - depletion~ glucose + insulin - loading) or by preconditioning, with 5 min ischaemia and 5 min reperfusion prior to sustained ischaemia. Results: Analysis of glucose uptake relative to delivery showed that in severe low flow ischaemia, the extraction of glucose was increased, and glycolysis was thus limited more by substrate supply than by enzyme inhibition. Analysis of metabolites confirmed this concept. The optimal glucose concentration during severe low flow ischaemia was 11 mM, giving maximal recovery on reperfusion. Both lower and higher glucose concentrations increased ischaemic contracture. Changes in pre-ischaemic glycogen levels correlated with the time to onset of contracture, such that a reduction in glycogen accelerated contracture. Prior glycogen depletion or loading did not improve functional recovery. The benefits of preconditioning on reperfusion function following sustained total global ischaemia could not be related to glycogen depletion. If preconditioning were followed by sustained low flow ischaemia, glucose uptake was increased, but no benefit was found, possibly because a low residual flow abolished the effects of preconditioning. Many of the above results are consistent with the hypothesis that too low a rate of glycolysis results. in insufficient ATP production for protection, while excess glycolytic rates lead to excess metabolite accumulation with detrimental effects. Conclusions: Provision of glucose at the correct concentration, when the benefit associated with glycolytic ATP outweighs the detriment associated with moderate metabolite accumulation, is protective to the low-flow ischaemic myocardium, which can upregulate its ability to extract glucose. Improved residual flow enhances this benefit. Prior glycogen depletion is not beneficial, despite a reduced metabolite accumulation. This mechanism cannot be related to the protective effect of preconditioning.
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    Preconditioning and augmented preconditioning via manipulation of metabolic and signalling pathways in the rat heart
    (2000) Makaula, Siyanda S S; Opie, Lionel H; Sack, Michael N
    Cardiac ischaemic preconditioning (IPC) describes a biological phenomenon whereby a short ischaemic stimulus confers protection to the heart against subsequent prolonged ischaemia and reperfusion injury. Understanding this survival programme will enable us to augment tissue tolerance against cell death. Ischaemic preconditioning is poorly understood, however, certain metabolic events and activation intracellular signalling events are known to trigger this cardioprotection. The purpose of this study was to investigate the metabolic and intracellular signalling events which occur during ischaemic preconditioning and their effects on improvement of contractile recovery following an ischaemia/reperfusion insult.