Until now, catecholamines were the drugs of choice to treat hypotension during shock states. Catecholamines, however, also have marked metabolic effects, particularly on glucose metabolism, and the degree of this metabolic response is directly related to the beta2-adrenoceptor activity of the individual compound used. Under physiologic conditions, infusing catecholamine is associated with enhanced rates of aerobic glycolysis (resulting in adenosine triphosphate production), glucose release (both from glycogenolysis and gluconeogenesis), and inhibition of insulin-mediated glycogenesis. Consequently, hyperglycemia and hyperlactatemia are the hallmarks of this metabolic response. Under pathophysiologic conditions, the metabolic effects of catecholamines are less predictable because of changes in receptor affinity and density and in drug kinetics and the metabolic capacity of the major gluconeogenic organs, both resulting from the disease per se and the ongoing treatment. It is also well-established that shock states are characterized by a hypermetabolic condition with insulin resistance and increased oxygen demands, which coincide with both compromised tissue microcirculatory perfusion and mitochondrial dysfunction. This, in turn, causes impaired glucose utilization and may lead to inadequate glucose supply and, ultimately, metabolic failure. Based on the landmark studies on intensive insulin use, a crucial role is currently attributed to glucose homeostasis. This article reviews the effects of the various catecholamines on glucose utilization, both under physiologic conditions, as well as during shock states. Because, to date (to our knowledge), no patient data are available, results from relevant animal experiments are discussed. In addition, potential strategies are outlined to influence the catecholamine-induced effects on glucose homeostasis.
The fluxes of arginine and citruiline through plasma and the rate of conversion of labeled citrulline to arginine were estimated in two pilot studies (with a total of six adult subjects) and in a dietary study with five healthy young men. These latter subjects received an L-amino acid-based diet that was arginine-rich or arginine-free each for 6 days prior to conduct, on day 7, of an 8-hr (first 3 hr, fast; final 5 hr, fed) primed continuous intravenous infusion protocol using L- [guandno-93C]arginine, L-[5,5-2H2]citrulline, and L- [5,5,5-2H31leucine, as tracers. A pilot study indicated that citrulline flux was about 20% higher (P < 0.05) when determined with [ureido-13C]citrulline compared with [2H2Jcitruline, indicating recycling of the latter tracer. Mean citruilin fluxes were about 8-11 pmol kg'lhr'1 for the various metabolic/diet groups and did not differ significantly between fast and fed states or arginine-rich and arginine-free periods. Arginine fluxes (mean ± SD) were 60.2 ± 5.4 and 73.3 ± 13.9 jAmol kg"l hr'1 for fast and fed states during the arginine-rich period, respectively, and were significantly lowered (P < 0.05), by 20-40%, during the arginine-free period, especially for the fed state, where this was due largely to reduced entry of dietary arginine into plasma. The conversion of plasma citruiline to arginine approximated 5.5 ,umol*kg'l-hr-1 for the various groups and also was unaffected by arginine intake. Thus, endogenous arginine synthesis is not markedly responsive to acute alterations in arginine intake in healthy adults. We propose that argmine homeostasis is achieved largely via modulating arginine intake and/or the net rate of arginine degradation.The physiological needs by tissues and organs for arginine are met via the endogenous synthesis of arginine and/or arginine supplied by the diet. For the U.S. population the latter amounts to about 5.4 g daily per capita (1). The rates of endogenous arginine synthesis in the immature rat (2, 3), guinea pig (4), cat (5, 6), dog (7-9), chicken (10), rabbit (11), and pig (12) of nitric oxide (16) and of creatine and its participation as arginyl-tRNA in the process of ubiquitin-dependent protein degradation (17). Therefore, we have begun to use stableisotope tracer techniques to explore, noninvasively, kinetic and regulatory aspects ofarginine metabolism in adult human subjects (18,19). Here we report results of a study in young men who were given for 7 days an arginine-rich diet and then, for another 7 days, an arginine-free diet. Our kinetic model involves L-[guanidino-13C]arginine and L-[5,5-2H2]citrulline as tracers, to estimate plasma arginine and citrulline fluxes as well as the rate of transfer of plasma citrulline into the arginine pool. From the present findings, and our recent studies (19), we propose an integrative scheme of body arginine homeostasis and balance, which defines the metabolic basis for the conditional indispensability of dietary arginine under various pathophysiological conditions (1, 13, 14). MATERIALS AND METHOD...
During sepsis, excessive activation of the complement system with generation of the anaphylatoxin C5a results in profound disturbances in crucial neutrophil functions. Moreover, because neutrophil activity is highly dependent on intracellular pH (pH), we propose a direct mechanistic link between complement activation and neutrophil pH In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pH by selective activation of the sodium/hydrogen exchanger. Upstream signaling of C5a-mediated intracellular alkalinization was dependent on C5aR1, intracellular calcium, protein kinase C, and calmodulin, and downstream signaling regulated the release of antibacterial myeloperoxidase and lactoferrin. Notably, the pH shift caused by C5a increased the glucose uptake and activated glycolytic flux in neutrophils, resulting in a significant release of lactate. Furthermore, C5a induced acidification of the extracellular micromilieu. In experimental murine sepsis, pH of blood neutrophils was analogously alkalinized, which could be normalized by C5aR1 inhibition. In the clinical setting of sepsis, neutrophils from patients with septic shock likewise exhibited a significantly increased pH These data suggest a novel role for the anaphylatoxin C5a as a master switch of the delicate pH balance in neutrophils resulting in profound inflammatory and metabolic changes that contribute to hyperlactatemia during sepsis.
Urinary nitrate (NO3) is the stable end product of nitric oxide, which is formed, in turn, from a guanidino nitrogen of arginine. We have conducted two experiments, each in four healthy adult men receiving a low nitrate diet for 7-10 days, to investigate the in vivo conversion of arginine to nitrate.In the first study [guanidino-'5N2, 5,5-2H2]arginine was given on day 7 via a primed continuous intravenous infusion for 8 h. In the second study, the labeled arginine was given for 8 h by the intragastric route on day 7 and by the intravenous route on day 10. Measurement of 1IN03 output in urine collected for 24 h beginning at the time of the arginine tracer infusion revealed a more extensive transfer of 15N when the arginine tracer was given intragastricly. From the comparative labeling of 1IN03 after administration of the tracer arginine via the intragastric and intravenous routes, we estimate that 16% ± 2% of the daily production of nitrate arises from the metabolism of dietary arginine that is taken up during its "first pass" in the splanchnic region. Hence, nitric oxide production occurs, to a measurable extent, in this area in healthy subjects, raising the question as to how various pathophysiological states might alter the relations between exogenous and endogenous sources of arginine as precursors of NO-and the relative contributions made by various organs to whole body (NOB) NO3 formation. These results also raise important questions about the use of nitric oxide synthase inhibitors in animal and human studies.The endogenous synthesis of nitrate by mammals (1, 2) was demonstrated to occur via oxidation of trivalent nitrogen (i.e., amino nitrogen) and to be greatly stimulated by an endotoxin challenge (3). Studies by Marletta and coworkers (4, 5) with murine macrophages disclosed an enzymatic pathway that involved the oxidation of a guanidino nitrogen of L-arginine to nitric oxide (NO-) and its subsequent oxidation and excretion as urinary nitrate (e.g., refs. 6 and 7). Numerous other investigations concerning problems of cardiovascular physiology, neuronal signaling, and endotoxic shock have resulted in the discovery of a large family of NOsynthase enzymes (NOS; EC 1.14.23.-). These NOS include both constitutive and inducible forms and may be membrane bound or cytosolic depending on cell type; the physiological roles of these enzymes have been recently reviewed (8-11). In addition, reports have appeared recently on the isolation and cloning of some of the key genes encoding NOS (12-14), which revealed close sequence similarity to cytochrome P450 reductase (15) and also with functional characteristics of a P450-type hemoprotein (16). Thus, given the apparently large number of isoforms of NOS, their varying distribution in human tissues, and their multiple mechanisms of activation, it is of importance to define the in vivo relationships between arginine metabolism and urinary nitrate in man.In an earlier study, Leaf et al. (6) gave a large oral bolus dose (85 mg-kg-' of body weight) of [15N]arginine t...
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