Luc Cynober

Plasma amino acid levels with a note on membrane transport: characteristics, regulation, and metabolic significance

The plasma concentration of an amino acid (AA) is the result of its rates of appearance (Ra) in and disappearance (Rd) from plasma. As for most nutrients, AA Ra and Rd are tightly regulated and at the postabsorptive state Ra equals Rd. Factors controlling Ra are protein intake and tissue release; those controlling Rd are tissue uptake and body losses (urine, sweat, etc.). Regulation of plasma AA concentrations involves hormones, in particular insulin and glucagon, both of which induce hypoaminoacidemia (but for quite different reasons), and cortisol, which induces hyperaminoacidemia. In addition, in pathologic states, catecholamines, thyroid hormones, and cytokines modulate plasma AA levels. Peripheral availability of AAs after protein ingestion is controlled by the liver, with an activation of ureagenesis in hyperprotein feeding and repression during a hypoprotein diet. The arginine-to-citrulline pathway in the intestine plays a key role in this adaptative process. In some circumstances tissue uptake of AAs and further metabolism depend on plasma AA concentrations. Plasma glutamine level may be the driving force controlling the flux of this AA at the muscle level. Also, channeling of the arginine cellular pathways means that plasma arginine is a major controlling component of nitric oxide synthesis in endothelial and immune cells. All these features explain the excessive increase in glutamine and arginine demands, in particular for energy expenditure, leading to morbidity (e.g., gut atrophy, muscle wasting, and immune dysfunction) in stressed patients. Normoaminoacidemia is not synonymous with health because this state is observed in level 2 starvation (Ra and Rd decrease) or after minor injury (Ra and Rd increase). Hyperaminoacidemia may be the consequence of organ failure (Rd decreases) or excessive AA intake during parenteral nutrition (Ra increases). Hypoaminoacidemia is observed after organ removal (Ra decreases, e.g., decrease in citrulline concentration in short bowel syndrome) or in stress situations (Rd increases). Mere determinations of plasma AA concentrations at the basal state (i.e., postabsorptive) provide rather limited information. Their usefulness can be improved by measuring arteriovenous differences or performing time course measurements, but techniques based on stable isotopes are necessary to obtain more precise information on the behavior of a particular AA or group of AAs.

The feeding route (enteral or parenteral) affects the plasma response of the dipetide Ala-Gln and the amino acids glutamine, citrulline and arginine, with the administration of Ala-Gln in preoperative patients.

Enhancement of depressed plasma concentrations of glutamine and arginine is associated with better clinical outcome. Supplementation of glutamine might be a way to provide the patient with glutamine, and also arginine, because glutamine provides the kidney with citrulline, from which the kidney produces arginine when plasma levels of arginine are low. The aim of the present study was to investigate the parenteral and enteral response of the administered dipeptide Ala-Gln, glutamine, citrulline and arginine. Therefore, seven patients received 20 g Ala-Gln, administered over 4 h, parenterally or enterally, on two separate occasions. Arterial blood samples were taken before and during the administration of Ala-Gln. ANOVA and a paired t test were used to test differences (P<0.05). Ala-Gln was undetectable with enteral administration, whereas Ala-Gln remained stable at a plasma concentration of 268 micromol/l throughout parenteral infusion and rapidly decreased towards zero after infusion was stopped. The highest level of glutamine was observed with parenteral infusion of the dipeptide, although enteral infusion also significantly increased plasma levels of glutamine. The highest plasma response of citrulline was observed with the enteral administration of the dipeptide, although parenteral administration also increased plasma levels of citrulline. Plasma arginine increased significantly with parenteral infusion, but not with enteral administration of Ala-Gln. In conclusion, administrations of Ala-Gln, parenteral or enteral, resulted in an increased plasma glutamine response, as compared with baseline. Interestingly, in spite of the high availability of citrulline with enteral administration of the dipeptide, only parenteral infusion of Ala-Gln increased plasma arginine concentration.

l-Arginine treatment for severe vascular fetal intrauterine growth restriction: A randomized double-bind controlled trial☆

BACKGROUND & AIMSnInfants born with severe IUGR are exposed to higher neonatal mortality and morbidity rates, as compared with appropriate-for-gestational-age. They are exposed to a higher risk of developing chronic disease such as hypertension, coronary artery disease, obesity, and type 2 diabetes in adulthood. L-Arginine is a precursor of nitric oxide (NO) and may play a role in placental vascular mediation or local vasodilatation.nnnOBJECTIVEnThe current study was designed to determine whether oral supplementation of gravid patients suffering from severe intrauterine growth restriction (IUGR) with L-arginine, would enhance birth weight and/or decrease neonatal morbidity.nnnPATIENTS AND METHODSnForty-four patients with a singleton pregnancy who had been referred for IUGR detected by ultrasonic examination were included. Vascular IUGR was defined by fetal abdominal circumference less than or equal to the 3rd percentile, associated with abnormal uterine Doppler. After double-blind randomization, patients received either 14 g/day of L-arginine, or a placebo.nnnRESULTSnThe characteristics of the two groups of patients (IUGR with L-arginine vs IUGR with placebo) were similar upon randomization. There was no significant difference between the two groups concerning birth weight (1042+/-476 vs. 1068+/-452 g). At delivery, maternal and neonatal characteristics were similar in the two groups. There was no difference in the Clinical Risk Index for Babies (CRIB) score, the duration of ventilatory assistance, nor the delay between birth and full enteral feeding between the two groups.nnnCONCLUSIONnIn this study which is, at the best of our knowledge, the first double-bind, multicenter, randomized trial in this condition, L-arginine is not an effective treatment for severe vascular growth restriction.

Effect of aging on liver functions—an experimental study in a perfused rat liver model

BACKGROUNDnAging is associated with marked changes in the physiology of many organs. Aging of the liver has been little studied and findings are inconclusive. The purpose of this work was to determine the effect of aging on transport and metabolic functions of the liver as assessed by extraction ratio of indocyanine green (ICG) and urea flux respectively. Bile flow was also recorded. As ICG is removed exclusively by the liver without bioconversion, its clearance reflects hepatic functional mass.nnnMETHODSnLivers from adult (3-month old) or old (24-month old) rats were perfused in a recirculating system for 90 min. At time 30 min, a bolus of 0.125 mg of indocyanine green was introduced in the perfusion buffer. At least every 10 minutes, the perfusion buffer was sampled for the measurements of ICG and urea. Bile flow was closely monitored throughout the experiment.nnnRESULTSnExtraction ratio of ICG was increased in livers from old rats (9.49 +/- 2.84 vs 3.70 +/- 1.56% of ICG extracted), whereas urea flux was diminished (0.33 +/- 0.06 vs 1.33 +/- 0.65 micromol/min/% of ICG extracted) and bile flow was unchanged (4.03 +/- 1.02 vs 3.57 +/- 1.34 microl/min).nnnCONCLUSIONSnAging does not affect the different functions of the liver in the same way. It increases hepatocellular uptake function, but decreases the metabolic function of hepatocytes and does not change excretion function. These discrepancies are likely to be of some importance in the study of drug metabolism and action, and so we suggest that results should be corrected for ICG extraction.