RELATIONSHIPS OF PYRUVATE AND LACTATE DURING ANAEROBIC METABOLISM. I. EFFECTS OF INFUSION OF PYRUVATE OR GLUCOSE AND OF HYPERVENTILATION1

Abstract

When the supply of oxygen to the interior of living cells is reduced to a rate insufficient for their current metabolic needs for oxygen, then various cellular oxidation-reduction systems must shift toward a more reduced state. Thus, as the oxygen tension falls the "oxidation potential" ("Eh") decreases (1, 2), (the rate of decrease being a complex and variable function of Po2 and also of the rate of energy utilization), and the various redox systems shift toward their reduced forms in a sequence determined by their inherent redox characteristics (1), cytochrome oxidase, the cyto-chromes and their dependent systems, flavopro-teins and diphosphopyridine nucleotide (DPN). The lowest potential in the "carrier" system is that of DPN, which is the final electron donator and functions also in the "metabolic" oxidative systems; the rates of the oxidations of energy metabolism are not affected until DPN is affected. When the oxidative potential in the hypoxic cell has diminished to the level of the potentials of the "metabolic" systems, the first of these DPN-coupled systems to become reversed will be the one of potential closest to that of DPN: DPNH2, the lactic dehydrogenase (LDH) system. LDH 1) Pyruvate + DPNH2 I ' Lactate + DPN The fact that this system should shift toward the reduced state at the same time as the final transport system (DPN) appears to be an important arrangement of potentials from the point of view of the continuance of cell life during hypoxia. This is because the end-product of reduction in the LDH system is lactate, which has no other function in metabolism. All the other metabolic redox systems operate in series, so that the products of one system become the substrates of another , or several other, systems; if oxidation in 'Aided in part by a grant from the American Heart Association. one of these systems were to stop or slow down, the whole process of energy metabolism would be affected. The LDH system, however, is unique in being "dead-end;" endogenous lactate does not participate in any other equilibrium or enter into any other reaction which would be affected by its accumulation in the cell.2 Lactate is not the only product of a shift to the right in the steady state depicted by equation 1). Oxidized DPN also is produced from reduced DPN. Under conditions of true oxygen deficiency within the cell, then, as the oxidation of DPNH2 by molecular oxygen through the carrier system falls off, oxidation of DPNH2 by the LDH system takes up. If this substitution for oxygen could occur at a sufficient rate, the oxidative potential of the cell medium would fall no further, and the remainder of the oxidations of energy metabolism could therefore continue, and life would be sustained. If the systems at any other level of potential had a significant poising effect, the fall of "Eh" might be checked (1), but in those cells which have been studied this usually does not appear to be the case (1, 2), "Eh" falling to about-0.180, that of LDH. It is important to emphasize that the situations envisaged by this reasoning do not include 1) complete , or even nearly complete, absence of oxygen (which would halt the succinic system), or 2) the possible toxic effects of unlimited lactate and acid accumulation. It is true that most mammalian tissues cease to function or die in the total absence of oxygen. However, the survival of animals and human patients during a great variety of lesser hypoxic states, especially during cardiopulmonary 2 This assertion is not dependent solely on the failure to discover any other lactate reaction in mammalian tissues up to the present time (3), but is confirmed by the close parallelism of specific activities of lactate and py-ruvate from living tissue following exhibition of isotope tagged pyruvate (4, 5). 244