1 results for Armiger, Lois Clare

  • An Investigation of the rôle of lactic acid in myocardial infarction

    Armiger, Lois Clare (1973)

    Doctoral thesis
    The University of Auckland Library

    Restricted Item. Print thesis available in the University of Auckland Library or may be available through Interlibrary Loan. Three groups of experiments were carried out in order to explore some of the relationships between the fine-structural changes and the metabolic disturbances which occur in heart tissue during ischaemia. Firstly, the morphological changes were defined; secondly, the relationship of these changes to raised tissue lactic acid concentrations was established in vitro; and finally, the latter findings were confirmed in vivo. In 38 dogs, the circumflex branch of the left coronary artery was ligated for periods ranging from 5-720 minutes. In each case tissue from the posterior papillary muscle, which is rendered ischaemic in this preparation, was compared with unaffected tissue from the anterior superior interventricular septum. Following 10-40 minutes of arterial occlusion the ischaemic tissue showed progressive fine-structural abnormalities. In addition to mitochondrial degeneration these included disappearance of glycogen granules, margination and clumping of nuclear chromatin, relaxation of myofibrils, increase in interfibrillar spaces and swelling of sarcoplasmic reticulum. After 60 minutes of ischaemia the mitochondrial changes were particularly striking, comprising marked swelling and loss of matrix density, disorganisation and breakdown of cristae, and the presence of dense inclusions. As there is a rapid accumulation of lactic acid in ischaemic heart muscle, an in vitro system was then devised to demonstrate the effects of raising the lactate ion concentration of myocardial tissue at physiological and at acid pH. Normal myocardium from 12 dogs was sliced at 250 µm and incubated for up to 190 minutes in isotonic, phosphate-buffered NaCl or in a similar solution incorporating 3,000 µg/ml of sodium lactate, at pH values ranging from 6.0 to 7.8. At various intervals tissue from control and lactate-containing media was fixed and examined by electron microscopy. After only 10 minutes' incubation, tissue exposed to the high lactate concentrations showed mitochondrial disorganisation, comparable in severity with that seen after 60 minutes of arterial occlusion in vivo. By the same time, intramitochondrial dense inclusions were present in tissue from media at pH 6.0-6.9 and pH 7.8, whereas in tissue from media at physiological pH, they developed much more slowly. To enable confirmation of these observations in vivo and under non-ischaemic conditions, a method of infusing substances into the blood supplying the posterior papillary muscle via a common carotid-circumflex artery shunt was developed and used in 34 dogs. When the tissue lactate concentration in the posterior papillary muscle was raised in this way to two or more times that of control myocardium, the mitochondria showed alterations similar to those induced under in vitro conditions by lactate at physiological pH. When the pH of the blood supplying the posterior papillary muscle was decreased to less than 7.0 by infusion of acidified saline, the mitochondria showed only mild swelling and loss of matrix density but many contained dense inclusions. These experiments demonstrated that the mitochondrial degenerations seen in ischaemic myocardial cells are related to the accumulation of lactic acid, that the gross swelling of the organelles is associated primarily with an increase in lactate anions, and that the formation of dense inclusions is associated with lowered tissue pH.

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