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The effects of hypoxia, ischaemia and inotropic interventions on mammalian cardiac muscle

Lee, John Andre; (1990) The effects of hypoxia, ischaemia and inotropic interventions on mammalian cardiac muscle. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Variations in intracellular Ca2+ concentration ([Ca2+]i) are responsible for much of the modulation of the force of contraction in cardiac muscle. However, in many situations, changes in the sensitivity of the contractile proteins to Ca2+ also contribute to alterations of force. If [Ca2+]i and force production are measured simultaneously, it is possible to identify the contribution of these processes to the changes in the force of contraction produced by various interventions. Two interventions of clinical importance are hypoxia and ischaemia. Their effects were studied in thin ventricular papillary muscles, which were microinjected with the photoprotein aequorin in order to measure [Ca2+]i. During an initial exposure to hypoxia, the systolic rise of [Ca2+]i (the Ca2+ transient) often showed a moderate increase, but on subsequent exposures this increase disappeared and eventually the Ca2+ transient declined on exposure to anoxia. This decline could be converted back to an increase by exposure to an elevated glucose concentration, suggesting that the response was dependent on the metabolic state of the muscle. This was confirmed in a parallel series of experiments in which glycogen and lactate production were measured in Langendorff-perfused hearts exposed to hypoxia. Ischaemia has previously been difficult to study in isolated cardiac muscle. A new model was developed which allowed ischaemia to be mimicked in an isolated papillary muscle while [Ca2+]i was measured. Ischaemia caused a dramatic decline in tension, and a large increase in the amplitude of the Ca2+ transients developed over several minutes. These changes could be mimicked by the application of 20 mM lactic acid. After long exposures to ischaemia, resting tension developed and the Ca2+ transients declined. Repeated exposures to ischaemia caused an early fall in the Ca2+ transients, and the early development of resting tension and raised resting Ca2+. Thus, many of the effects of hypoxia and ischaemia seem to be attributable to an intracellular acidosis due to lactic acid accumulation, which is more severe in ischaemia due to the lack of flow. The severity of the acidosis depends on the initial metabolic state of the tissue. Although past laboratory studies have concentrated on isometric contraction, in vivo the heart has phases of both isotonic as well as isometric contraction, and modern use of cardiac myocytes means that unloaded preparations are now frequently studied. The effects of several positive and negative inotropic interventions on isotonic and isometric contraction were compared. For all interventions, the fractional effect on tension was 1.5 - 2 times larger than that on shortening, and this could be accounted for by the shape of the length- force relation for cardiac muscle in different inotropic states. Pimobendan is a new inotropic agent, which is thought to have both Ca2+ sensitising and phosphodiesterase inhibiting activity. Its effects on tension and Ca transients were studied. The results suggest that both these effects are active in living cardiac muscle, and that this combination may be advantageous for an inotropic agent. These experiments have demonstrated that changes in both the Ca2+ transient and Ca2+ sensitivity occur when cardiac muscle is exposed to hypoxia or ischaemia. The effects of interventions on isometric force and shortening are similar. Finally, drugs are now available which can alter Ca2+ sensitivity as well as the Ca2+ transient.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The effects of hypoxia, ischaemia and inotropic interventions on mammalian cardiac muscle
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Cardiac muscle
URI: https://discovery.ucl.ac.uk/id/eprint/10124742
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