Ion Gradients And Metabolic Energy In Animal Tissue

Veech, Richard

Abstract

The energy of the gradients of the nine major inorganic ions in working perfused heart are in near equilibrium with each other, the electrical potential between extra- and intracellular phase and the delta G of ATP hydrolysis [Masuda T et al, J Biol Chem 1990;265:20321-34]. The metabolism of ethanol increases the resting electrical potential of hepatocytes from -28 to -40 mV [Veech RL et al, Alch Clin Exp Res 1994;18:1040-56]. Previously, we showed that merely changing the substrate available altered the delta G of ATP hydrolysis in heart and improved the efficiency of hydraulic work of heart by 28% [Kashiwaya Y et al, Am J Cardiol 1997;80:50A-64A]. Since injuries of any sort induce a stereotypic change in cellular ionic distributions wherein the cell gains Na+, loses K+ and swells, these stereotypic changes of injury can possibly be reversed by simple changes in the compositions of fluids administered to victims of injury or burns. We went on to show that the gradients of all nine common inorganic ions between intra and extracellular phases of a cell form a Donnan near equilibrium system relating the electrical potential between the phases to the energy of ATP hydrolysis [Veech RL et al, IUBMB Life 2002;54:241-52]. As a result of these studies and our earlier studies criticizing the composition of existing parenteral fluids [Veech RL, Am J Clin Nutr 1986;44:519-51] a panel convened by the Academy of Medicine, recommended that investigation of the feasibility of making new resuscitation fluids be initiated [Fluid Resuscitation, Natl Acad Press, Wash DC, 1999]. ? ? We have taken part in these studies sponsored by the Department of Defense since that time. The goal is to improve the standard treatment of hemorrhage and burns, which has not changed over the past 50 years. We had earlier shown that the d isomer of lactic acid, a component in Ringers Lactate, induced cardiac arrythmias in children undergoing resuscitation from burn and could induce fatal arrythmias in experimental animals [Chan L et al, Physiol Behav Sci 1994;29:383-94]. In collaboration with the Naval Blood Research Laboratory, we designed and caused to be manufactured alternatives Ringer's solutions for use in resuscitation from hemorrhage in experimental animals. Tests of these newly manufactured fluids performed at USUHS have shown that resuscitation from hemorrhage with the standard high volume Ringer's lactate protocol leads to apoptosis in the lung 24 hours after hemorrhage and that this untoward effect can be avoided if Na D-?O-hydroxybutyrate is substituted for the D,L-lactate in such fluids [Alam HB et al, J Am Col Surg 2001;193:255-63]. Lung damage after resuscitation, so called DaNang lung was a leading cause of post surgical death during the Viet Nam war. Although not admittedly, during 2003, the US fluid manufacturers changed the composition of Ringer's lactate from D,L to L lactate. This change was not done through submission of new data to FDA, but rather through the expedient of changing the definition of lactate in the US Pharmacopeia from a substance without optical rotation, to one with optical rotation.? ? The inclusion of L-lactate in parenteral fluids, while an improvement over fluids containing D,L-lactate, is not optimum. Conditions requiring resuscitation are almost inevitably associated with hypoxia and lactic acidosis. Additional infusion of L-lactate worsens this condition and adds to the blockade of glycolysis, the major source of energy generation during periods of hypoxia as has been shown in studies by collaborators [Cross HR et al, J Mol Cell Cardiol 1995;27:1369-81]. It is our opinion that resuscitation fluids containing D-?O-hydroxybutyrate in place of L-lactate are preferable. In collaboration with the Naval Blood Laboratory, we are attempting to design and prepare such fluids made under cGMP conditions for testing in human subjects. A manuscript entitled """"""""Severe adverse events associated with hemoglobin based oxygen carriers: role of resuscitative fluids and liquid preserved RBC"""""""" detailing the toxic effects of current resuscitation practices and how they can be avoided has been accepted for publication in the Journal of Trauma.? ? ? SIGNIFICANCE OF THIS WORK TO THE PROGRAMS OF THIS INSTITUTE? Ingestion of alcohol reduces the free [NAD+]/[NADH] ratio in cytoplasm of liver as does intravenous administration of l-lactate. Therefore this work has some significance to the work of this institute. However, this work is of greater significance to medical and surgical treatments in general particularly to the treatment of those engaged in combat or subject to injury from mass disasters.