Control of proteolysis in perifused rat hepatocytes

AbstractThe mechanism by means of which amino acids inhibit intrahepatic protein degradation has been studied in perifused rat hepatocytes. Proteolysis was extremely sensitive to inhibition by low concentrations of amino acids. A mixture of 0.5 mM leucine and 1–2 mM alanine, concentrations found in the portal vein of the rat after feeding, inhibited proteolysis to the same extent as a complete physiological mixture of amino acids. Inhibition by these two amino acids was accompanied by a rise in the intracellular concentrations of glutamate and aspartate, and was largely prevented by addition of glucagon, by addition of the transaminase inhibitor aminooxyacetate, or by omission of K+. Acceleration of proteolysis by K+ depletion was accompanied by a fall in intracellular glutamate caused by an increased rate of transport of this amino acid to the extracellular fluid. It is concluded that intracellular leucine, glutamate and aspartate are important elements in the control of hepatic protein degradation

Impact of metformin on peak aerobic capacity

Individually, exercise and the drug metformin have been shown to prevent or delay type 2 diabetes. Metformin mildly inhibits complex I of the electron transport system and may impact aerobic capacity in people exercising while taking metformin. The purpose of the study was to evaluate the effects of metformin on maximal aerobic capacity in healthy individuals without mitochondrial dysfunction. Seventeen healthy, normal-weight men (n=11) and women (n=6) participated in a double-blind, placebo-controlled, cross-over design. Peak aerobic capacity was measured twice using a continuous, incrementally graded protocol; once after 7-9 d of metformin (final dose=2000 mg/d) and once with placebo, with 1 week between tests. The order of the conditions was counterbalanced. Peak oxygen uptake (VO2 peak), heart rate (HR), ventilation (VE), respiratory exchange ratio (RER), rating of perceived exertion (RPE), and test duration were compared across conditions using paired t tests with the R statistical program. VO2 peak (-2.7%), peak heart rate (-2.0%), peak ventilation (-6.2%), peak RER (-3.0%), and exercise duration (-4.1%) were all reduced slightly, but significantly, with metformin (all p\u3c0.05). There was no effect of metformin on RPE or ventilatory breakpoint. Correlations between the decrement in VO2 peak and any of the other outcome variables were weak (r2\u3c0.20) and not significant. Short-term treatment with metformin has statistically significant, but physiologically subtle, effects that reduce key outcomes related to maximal exercise capacity. Whether this small but consistent effect is manifested in people with insulin resistance or diabetes who already have some degree of mitochondrial dysfunction remains to be determined

The relationship between blood lactate and survival following the use of adrenaline in the treatment of septic shock

This prospective observational study evaluates the relationship between adrenaline, lactate and intensive care unit survival in septic shock. Forty patients requiring adrenaline therapy for a first episode of septic shock acquired >24 hours after admission to the intensive care unit had blood lactate levels measured two-hourly over a 24-hour period. Adrenaline therapy was escalated until target mean arterial pressure was reached. The lactate index was calculated as the ratio of maximum lactate increase to the adrenaline increase. Lactate increased from 2.3 to 2.9 mmol.l (P=0.024) and the mean adrenaline increase was 0.14 μg.kg.minute. Peak lactate correlated with peak adrenaline (rho=0.34, P=0.032). Lactate index was the only independent predictor of survival after controlling for age and Acute Physiological and Chronic Health Evaluation II score (odds ratio 1.14, 95% confidence interval 1.03 to 1.26, P=0.009). A high lactate following adrenaline administration may be a beneficial and appropriate response

Acid-base and bio-energetics during balanced versus unbalanced normovolaemic haemodilution

Fluids balanced to avoid acid-base disturbances may be preferable to saline, which causes metabolic acidosis in high volume. We evaluated acid-base and bio-energetic effects of haemodilution with a crystalloid balanced on physical chemical principles, versus crystalloids causing metabolic acidosis or metabolic alkalosis. Anaesthetised, mechanically ventilated Sprague-Dawley rats (n=32, allocated to four groups) underwent six exchanges of 9 ml crystalloids for 3 ml/blood. Exchange was with one of three crystalloids with strong ion difference (SID) values of 0, 24 (balanced) and 40 mEq/l. Controls did not undergo haemodilution. Mean haemoglobin concentration fell 11 to approximately 50 g/l after haemodilution. With SID 24 mEq/l fluid, metabolic acid-base remained unchanged. Dilution with SID 0 mEq/l and 40 mEq/l fluids caused a progressive metabolic acidosis and alkalosis respectively. Standard base excess (SBE) and haemoglobin concentration were directly con-elated in the SID 0 mEq/l group (R-2 = 0.61), indirectly correlated in the SBE 40 mEq/1 group (R-2 = 0.48) and showed no correlation in the SID 24 mEq/l group (R-2=0.003). There were no significant differences between final ileal values of CO2 gap, nucleotides concentration, energy charge, or luminal lactate concentration. SID 40 mEq/l crystalloid dilution caused a significant rise in subcutaneous lactate. In this group mean kidney ATP concentration was significantly less than controls and renal energy charge significantly lower than SID 0 mEq/l and control groups. We conclude that a crystalloid SID of 24 mEq/l provides balanced haemodilution. Bio-eneigetic perturbations with higher SID haemodilution may be more severe and need further investigation