Ion Gradients And Metabolic Energy In Animal Tissue

点击翻译按钮获取中文摘要

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 DG 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, Alcoholism Clin Exp Res 1994;18:1040-56). Previously, we showed that merely changing the substrate available altered the DG of ATP hydrolysis in heart (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. As a result of these studies and our suggestions to a panel convened by the Academy of Medicine, a recommendation has been made that investigation of the feasibility of making new resuscitation fluids be initiated (see: Fluid Resuscitation, state of the science for treating combat casualties and civilian injuries, National Academy Press, 1999). The goal is to improve the standard treatment of hemorrhage and burns, which has not changed over the past 50 years. We are collaborating in this effort with the Naval Blood Research Lab. Our manuscript relating the Delta G of ATP hydrolysis to the energy of the gradients of all 9 common inorganic ions between extra and intracellular phases of heart, liver and red blood cell has now been accepted for publication. These tissues differ in electrical potential from -86 to -28 to -6 mV. We found that the energy of the Na+ gradient was about 1/3 of the energy of ATP hydrolysis and that the resting membrane potential as measured by KCl microelectrodes was a work function required to electrophoresis the most permeant ion. The system of ion gradients therefore appears to be a Gibbs Donnan near-equilibrium system dependent upon the energy of ATP hydrolysis. This has led to the preparation and testing of a new family of parenteral fluids for use in hemorrhage, resuscitation, head trauma, stroke and the treatment of burns in both military and civilian settings. In military settings, half of all fatal wounds are the result of head trauma. Accordingly, we have designed new fluids for the treatment of head trauma associated with hemmorhage. In collaboration with the Office of Naval Research, these new fluids are currently being evaluated in animal models in four different laboratories across the country to determine if these new fluid decrease morbidity and mortality. In addition, in collaboration with the Naval Blood Research Laboratory and the Dept of Critical Care Medicine at Johns Hopkins, we have developed new fluids for the treatment of two hour occlusion of the middle cerebral artery. These new treatments will be compared with existing treatments over the course of the coming year to determine if the new fluids decrease the cell death and apoptosis following transient ischemia induced by occlusion of the middle cerebral artery. Finally, we have continued and extended our work on the determination of free [Mg2+], in collaboration with the BHF NMR laboratory in Oxford by determining the free [Mg2+] in red cells from patients with sickle cell anemia. Administration of Mg had been proposed as a therapy for sickle crisis. We showed in this paper, that previous reports of the levels of free [Mg2+] being elevated were incorrect due to loss of ATP with result decrease in Mg2+ binding. These observations should be of value in determining appropriate therapy in sickle crisis. This manuscript has now been accepted for publication.