Hypoxia is probably the most common cause of lactic acidosis in man and the mortality can be as high as 90%. The goals of the present proposal are to elucidate the pathogenesis of hypoxic lactic acidosis in vivo in the dog and to specifically determine the effects of hypoxic lactic acidosis on isolated hepatocytes in vitro in the rat. The specific detrimental effects of NaHCO3 in lactic acidosis will be investigated both in vivo and in vitro, and the effects of other forms of therapy, such as volume expansion, reversal of hypoxia or dichloroacetate will be evaluated. We have developed a model of hypoxic lactic acidosis in the anesthetized dog. Blood lactate levels of about 3 mM, 8 mM, and above 12 mM can be produced by graded degrees of hypoxia (arterial pO2 of 25-40 mmHg). The in vivo studies will include evaluation of intracellular pH (pHi)2 in heart, skeletal muscle and liver where pHi will be measured both by use of 14C labelled DMO and serially by use of nuclear magnetic resonance (NMR). Lactate production by tissues (gut, brain, muscle) will be evaluated by A-V lactate gradients X organ blood flow, while tissue uptake of lactate (kidney, liver) and oxygen (gut, muscle, kidney, liver) will be determined by A-V gradients X organ blood flow. Serial measurements will also be made of cardiac output, tissue (muscle, liver) redox state and levels of lactate, pyruvate, bicarbonate and pO2, pCO2 and pH in blood from aorta and renal, femoral, hepatic and hepatic portal veins. In vitro studies in cultured hepatocytes will be performed to isolate the specific effects of specific pertubations. These are hypoxia, alteration in pHi independent of hypoxia, insulin, the increment in pHi due to amino acids, and dichloroacetate. Lactate consumption and pHi will be determined in this culture system. The in vivo studies should enable us to determine the pathogenesis of hypoxic lactic acidosis in terms of alterations in cardiac function, overproduction of hypoxic lactic acidosis in terms of alterations in cardiac function, overproduction of lactic acid versus decreased consumption of lactate (by liver and kidney), and the interrelationships between pHi, tissue redox state and organ blood flow to production and metabolism of lactate. The in vitro studies should enable us to determine specific effects on the liver in terms of biochemical abnormalities. The possible detrimental effects of NaHCO3 can be evaluated in terms of the aforementioned variables, and the effects of other therapeutic maneuvers will be determined. It is hoped that the findings from these in vivo and in vitro studies can be applied to the understanding and treatment of hypoxic lactic acidosis in humans.
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