CONTROL OF PROTEIN AND ENERGY METABOLISM BY EPINEPHRIN

点击翻译按钮获取中文摘要

The original aims of the grant were (a) to define using amino acid tracers, the physiologic mechanism by which epinephrine lowers amino acid levels, (b) to determine whether epinephrine is an important affector of chronic stimulation of energy expenditure and alteration of substrate levels as is seen in stress and trauma, and (c) to determine the substrates which supply the energy for the increased metabolic rate induced by epinephrine beyond the initial acute burst. These aims have been addressed in humans in three clinical studies, two of which have been published and one of which has been submitted for publication. In addition, we have extended our leucine kinetic studies to address the effect of using a different tracer upon leucine kinetic measurements that bear upon the disposal of amino acids for protein synthesis. The purpose of aim 1 was to define how epinephrine lowers amino acid plasma concentrations in humans: through increased removal from the system or decreased appearance of amino acids from protein breakdown. We infused epinephrine and measured leucine and phenylalanine kinetics. We determined that epinephrine acutely affects both rates of amino acid appearance and disappearance, with the net effect being a net increase in amino acid removal. However, the effect of epinephrine on amino acid kinetics was transient, but chronic in lowering amino acid concentrations. These results suggest that the effect of epinephrine infusion on amino acid metabolism is to increase the metabolic efficiency of amino acid metabolism allowing rates of amino acid flux to proceed normally, but at lower concentrations of plasma amino acids. In a follow-up study using the same stable isotopically labeled tracers, we infused amino acids to replace the concentrations which had been suppressed by infusion of epinephrine. This situation was designed to be similar to that used in parenteral nutrition of critically ill patients. Again, we found no catabolic effect of epinephrine upon amino acid metabolism and no negative effect upon delivery of intravenous amino acids as parenteral nutrition. These results indicate no deleterious effect of elevation of epinephrine upon amino acid and protein metabolism. If anything, epinephrine may promote retention of protein, rather than its wasting in stress and trauma. In another study addressing the question of epinephrine's effect on energy expenditure, normal subjects were infused for 24-h with saline, then for 23-h with epinephrine to increase plasma epinephrine concentrations into the high physiologic range. Infusion of epinephrine transiently increased heart rate and blood pressure, but significantly increased energy expenditure for the duration of the epinephrine infusion. Infusion of epinephrine also produced a transient increase in urine flow and in urinary nitrogen excretion. This diuresis was compensated by a drop in urine volume and nitrogen excretion after the epinephrine infusion was stopped. We concluded that epinephrine can produce a chronic increase in energy expenditure and that the fuel for this increase was from increased carbohydrate oxidation, not fat or protein. The results of these studies indicate that elevated epinephrine is not detrimental in stress and trauma with respect to maintaining protein stores, nor is the increase in energy expenditure produced harmful as long as energy intake is provided in the form of enteral or parenteral nutrition. We are in the process of completing a follow up study on the route of disposal of amino acids that is increased by epinephrine. To do this study, we need to be able to measure protein synthesis directly. We have begun developing these techniques, but the methods require a [1,2-13C2]leucine tracer compared to the [1-13C]leucine tracer we used in the above studies. The problem is that the 13C located in the 2nd carbon is not metabolized directly as is the 1st carbon during decarboxylation of ketoisocaproic acid. Thus, leucine oxidation will not necessarily be measured the same using the different tracers. We are completing a study addressing these differences between the two tracers. When the study is completed we will be able to define the difference between the metabolic oxidation of the two tracers and define the pathway of the 2nd carbon through its more convoluted route of metabolism.