The Lactate/Pyruvate Ratio of Metabolic Modulation Using Glucose Insulin Kalium and Lactate Solution and Their Effect on Functional Mechanical Recovery of the Isolated Perfused Heart

Metabolic modulation with Glucose Insulin Kalium (GIK) solution has beenreally well known in their capacity to improve post ischemic heart function. In this regardGIK intervention on post operative Coronary Artery Bypass Graft (CABG) can improveheart function recovery on reperfusion period (Goldhaber dan Weiss, 1992; Atwell et al.,1997). Post operative CABG intervention with GIK will produce a beneficial effect onthe elevation of heart energy to prevent ionic homeostasis disturbance and reactiveoxygen species (ROS) production that become the basis of reperfusion injury (Silvermandan Stern, 1994; Cross et al., 1995; Taegtmeyer et al., 1997; Opie, 1999; Lazar, 2002;Doenst et al., 2003; Trence et al., 2003).Many efforts have been made to clarify how exactly GIK works to improve postischemic heart function as in CABG. This is crucially done in order to be able to modifythe solution concerned. Although this solution has been clearly proved to improve postischemic heart function, it is not totally free from its adverse effect. Its main side effect isthat it can provoke hyperglycemic state, which contrasts with the tight glucose control incontinuously normal range for the patients who are critically ill.In this study lactate and pyruvate level in the coronary effluent were measuredfrom the isolated heart directly perfused with GIK and lactate. It was shown that thepreischemic lactate level was low and then clearly elevated as soon as the reperfusiontook place due to anaerobic metabolism. In accordance with reperfusion time lactate leveldecreased gradually. In relation with pyruvate level, this substrate evolution looked likethe appearance of lactate but its value was lower if compared with lactate.The recovery in functional mechanical activity of the post ischemic heart seems tobe much more related to the pattern of the evolution of logarithmic lactate/pyruvate ratio(L/P ratio). Logarithmic value of L/P ratio in GIK group increased since the earlyreperfusion period (+40%, p < 0.05), followed by improvement in recovery ofmechanical activity in this group which was significantly higher if compared with thecontrol group. Similar fashion was found in lactate group in regard to the evolution of thelogarithmic value of L/P ratio in this group, where its value was significantly highercompared with the control group. The logarithmic evolution pattern on L/P ratio for thisgroup increased along the reperfusion time (+34% p < 0.05).From the present study, it can be concluded that the recovery of functionalmechanical activity of the post ischemic heart perfused with GIK is through modificationon cellular lactate metabolism

Ubiquinone Analogs: A Mitochondrial Permeability Transition Pore-Dependent Pathway to Selective Cell Death

International audienceBACKGROUND: Prolonged opening of the mitochondrial permeability transition pore (PTP) leads to cell death. Various ubiquinone analogs have been shown to regulate PTP opening but the outcome of PTP regulation by ubiquinone analogs on cell fate has not been studied yet. METHODOLOGY/PRINCIPAL FINDINGS: The effects of ubiquinone 0 (Ub(0)), ubiquinone 5 (Ub(5)), ubiquinone 10 (Ub(10)) and decyl-ubiquinone (DUb) were studied in freshly isolated rat hepatocytes, cultured rat liver Clone-9 cells and cancerous rat liver MH1C1 cells. PTP regulation by ubiquinones differed significantly in permeabilized Clone-9 and MH1C1 cells from that previously reported in liver mitochondria. Ub(0) inhibited PTP opening in isolated hepatocytes and Clone-9 cells, whereas it induced PTP opening in MH1C1 cells. Ub(5) did not affect PTP opening in isolated hepatocytes and MH1C1 cells, but it induced PTP opening in Clone-9 cells. Ub(10) regulated PTP in isolated hepatocytes, whereas it did not affect PTP opening in Clone-9 and MH1C1 cells. Only DUb displayed the same effect on PTP regulation in the three hepatocyte lines tested. Despite such modifications in PTP regulation, competition between ubiquinones still occurred in Clone-9 and MH1C1 cells. As expected, Ub(5) induced a PTP-dependent cell death in Clone-9, while it did not affect MH1C1 cell viability. Ub(0) induced a PTP-dependent cell death in MH1C1 cells, but was also slightly cytotoxic in Clone-9 by an oxidative stress-dependent mechanism. CONCLUSIONS/SIGNIFICANCE: We found that various ubiquinone analogs regulate PTP in different ways depending on the cell studied. We took advantage of this unique property to develop a PTP opening-targeted strategy that leads to cell death specifically in cells where the ubiquinone analog used induces PTP opening, while sparing the cells in which it does not induce PTP opening

Acute Inhibition of Selected Membrane-Proximal Mouse T Cell Receptor Signaling by Mitochondrial Antagonists

T cells absorb nanometric membrane vesicles, prepared from plasma membrane of antigen presenting cells, via dual receptor/ligand interactions of T cell receptor (TCR) with cognate peptide/major histocompatibility complex (MHC) plus lymphocyte function-associated antigen 1 (LFA-1) with intercellular adhesion molecule 1. TCR-mediated signaling for LFA-1 activation is also required for the vesicle absorption. Exploiting those findings, we had established a high throughput screening (HTS) platform and screened a library for isolation of small molecules inhibiting the vesicle absorption. Follow-up studies confirmed that treatments (1 hour) with various mitochondrial antagonists, including a class of anti-diabetic drugs (i.e., Metformin and Phenformin), resulted in ubiquitous inhibition of the vesicle absorption without compromising viability of T cells. Further studies revealed that the mitochondrial drug treatments caused impairment of specific membrane-proximal TCR signaling event(s). Thus, activation of Akt and PLC-γ1 and entry of extracellular Ca2+ following TCR stimulation were attenuated while polymerization of monomeric actins upon TCR triggering progressed normally after the treatments. Dynamic F-actin rearrangement concurring with the vesicle absorption was also found to be impaired by the drug treatments, implying that the inhibition by the drug treatments of downstream signaling events (and the vesicle absorption) could result from lack of directional relocation of signaling and cell surface molecules. We also assessed the potential application of mitochondrial antagonists as immune modulators by probing effects of the long-term drug treatments (24 hours) on viability of resting primary T cells and cell cycle progression of antigen-stimulated T cells. This study unveils a novel regulatory mechanism for T cell immunity in response to environmental factors having effects on mitochondrial function

Predicting cardiorespiratory instability

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901

International recommendations for glucose control in adult non diabetic critically ill patients

The purpose of this research is to provide recommendations for the management of glycemic control in critically ill patients.Comparative StudyJournal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishedPour la Société Française d'Anesthésie-Réanimation (SFAR); Société de Réanimation de langue Française (SRLF) and the Experts grou

Stimulation by glucose of gluconeogenesis in hepatocytes isolated from starved rats.

Control properties of the gluconeogenic pathway in hepatocytes isolated from starved rats were studied in the presence of glucose. The following observations were made. (1) Glucose stimulated the rate of glucose production from 20 mM-glycerol, from a mixture of 20 mM-lactate and 2 mM-pyruvate, or from pyruvate alone; no stimulation was observed with 20 mM-alanine or 20 mM-dihydroxyacetone. Maximal stimulation was obtained between 2 and 5 mM-glucose, depending on the conditions. At concentrations above 6 mM, gluconeogenesis declined again, so that at 10 mM-glucose the glucose production rate became equal to that in its absence. (2) With glycerol, stimulation of gluconeogenesis by glucose was accompanied by oxidation of cytosolic NADH and reduction of mitochondrial NAD+ and was insensitive to the transaminase inhibitor amino-oxyacetate; this indicated that glucose accelerated the rate of transport of cytosolic reducing equivalents to the mitochondria via the glycerol 1-phosphate shuttle. (3) With lactate plus pyruvate (10:1) as substrates, stimulation of gluconeogenesis by glucose was almost additive to that obtained with glucagon. From an analysis of the effect of glucose on the curves relating gluconeogenic flux and the steady-state intracellular concentrations of gluconeogenic intermediates under various conditions, in the absence and presence of glucagon, it was concluded that addition of glucose stimulated both phosphoenolpyruvate carboxykinase and pyruvate carboxylase activity