Hepatic Amino Nitrogen Conversion Research Articles

Acute effects of moderate dehydration on the hepatic conversion of amino nitrogen into urea nitrogen in healthy men

Acute effects of moderate dehydration on the hepatic conversion of amino nitrogen into urea nitrogen in healthy men

Acute effects of moderate dehydration on the hepatic conversion of amino nitrogen into urea nitrogen in healthy men

Intracellular hydration may play a role in the regulation of protein and nitrogen metabolism. The hepatic removal of nitrogen by urea synthesis has a key regulatory role in nitrogen balance. The purpose of the present study was to establish the acute effects of dehydration on the hepatic kinetics of urea synthesis, quantified by functional hepatic nitrogen clearance (FHNC), in healthy volunteers. Seven healthy men were studied twice in random order. On both study days, a primed continuous infusion of alanine was given. On the day of dehydration an intravenous bolus injection of a loop diuretic (furosemide, 1 mg/kg) was superimposed. FHNC was calculated as the ratio between measured synthesis rates of urea nitrogen and blood alanine concentrations. Furosemide induced a weight loss of 1 kg. During dehydration, FHNC decreased by approx. 25% (41+/-11 to 54+/-10 litres/h; P<0.02). On both occasions individual FHNC and glucagon values were positively correlated (r(2)>0.6). In addition, dehydration more than halved the linear slope of the relationship (P<0.05). The FHNC values were correlated with the urinary excretion of both potassium and sodium (r(2)=0.68, P<0.01 and r(2)=0.62, P<0.02 respectively). Changes in the reactivity of urea synthesis to glucagon (i.e. the ratio between FHNC and glucagon concentration) was negatively correlated with an indirectly estimated change in intracellular water (r(2)=0.79, P<0.05). We conclude that acute moderate dehydration down-regulates both total urea synthesis and its sensitivity to glucagon. The latter was related to estimated intracellular water loss. Dehydration may thus have nitrogen-saving consequences with regard to the hepatic contribution to whole-body nitrogen homoeostasis. The mechanism of this effect and the relationship with sodium and potassium fluxes is not known.

Hepatic amino- to urea-N clearance and forearm amino-N exchange during hypoglycemic and euglycemic hyperinsulinemia in normal man

Background/Aims: Hypoglycemia has well-described effects on glucose metabolism, whereas the possible effects on hepatic amino nitrogen conversion in relation to muscle amino nitrogen flux are more uncertain. Methods: We studied six healthy young male subjects three times, i.e. for 6 h in the basal state, during a 6-h euglycemic hyperinsulinemic (1.5 mU/kg/min) clamp and during a 6-h hypoglycemic (plasma glucose below 2.8 mmol/l) clamp. Alanine (2 mmol/kg body weight/h) was infused for 3 h to describe the relationship between blood amino nitrogen concentrations and hepatic ureagenesis estimated from urea urine excretion and accumulation in body water. The slope of this relationship is denoted functional hepatic nitrogen clearance (FHNC) and quantifies substrate-independent alterations in hepatic amino nitrogen degradation. In parallel, amino nitrogen balances across muscles were estimated by the forearm flux method. Results: Euglycemia decreased circulating glucagon values (100±25 ng/l vs. 160±30 ng/l), whereas hypoglycemia doubled glucagon (350±45 ng/l, p<0.05). Hepatic nitrogen clearance (FHNC) decreased during hyperinsulinemic euglycemia (19.5±3.4 1/h vs. 30.6±5.7 l/h, p<0.01), whereas forearm net uptake of amino nitrogen increased (130±40 nmol/100 ml7times;min vs. control: −10±4 nmol/100 ml7times;min). During hypoglycemia there was a 3-fold increase in hepatic nitrogen clearance up to 83.0±16.8 l/h ( p<0.01) and increased release of amino nitrogen from the forearm (−100±30 nmol/100 ml7times;min, p<0.01). Conclusion: Hypoglycemia in man induces a marked increase in hepatic amino- to urea-N clearance. This catabolic response to hypoglycemia in the liver may be of primary importance for muscle amino acid release. Our data are compatible with the notion that liver and muscle together are responsible for catabolism during hypoglycemia, and that glucagon may be the primary mediator via its effect on liver metabolism.

Hepatic amino nitrogen conversion and organ N-contents in hypothyroidism, with thyroxine replacement, and in hypethyroid rats

Background/Aims: The role of thyroid hormones in the regulation of hepatic conversion of amino nitrogen to urea is unresolved. The present study was designed to assess ureagenesis in rats with experimentally well-established hypo- and hyperthyroidism. The possible role of propylthiuracil (PTU), used for induction of hypothyroidism, was ascertained during thyroxine replacement of PTU treated hypothyroid rats. Methods: Basal blood amino nitrogen concentrations (AAN), the urea nitrogen synthesis rate (UNSR) and the maximal hepatic capacity for urea nitrogen synthesis (CUNS) obtained during alanine infusion were determined together with N-contents in the soleus muscle and kidneys in experimentally hypothyroid rats( n=19), upon thyroxine replacement ( n=14) and in experimentally hyperthyroid rats ( n=19). Hypothyroidism was induced by adding propylthiouracil (0.05%) to the drinking water for 5 weeks. Hyperthyroidism was induced by thyroxine 100 μg/100 g body weight. Results: During hyperthyroidism, T 3 fell to less than 10%, food intake was halved, and body weight fell by 13%. Basal blood AAN fell by 25% ( p<0.01), UNSR more than doubled ( p<0.01), and CUNS rose by 45% ( p<0.05). N-contents of the soleus muscle fell by 13% and by 20% in kidneys, respectively ( p<0.05). Thyroxine replacement normalized AAN, UNSR, CUNS and reduced N-loss to 7% in the soleus muscle (NS) and kidneys ( p<0.05), respectively. During hypethyroidism, T 3 rose fivefold, food intake rose by two thirds, and body weight fell by 10%. Basal AAN rose by 20% ( p<0.05), UNSR doubled ( p<0.01), and CUNS rose by 25% ( p<0.05). N-contents of the soleus muscle decreased by 19%, whreas kidney N-contents increased by 25% ( p<0.05). Overall liver function assessed by galactose elimination capacity did not differ among groups. Both conditions increased the rate of urea synthesis; in the hypothyroid state the hepatic waste of amino-N was limited by low blood concentration of amino-N, probably due to lower proteolysis. In the hyperthyroid state hepatic amino-N loss was aggravated by higher blood concentration of amino-N, probably due to higher proteolysis. This difference may explain the markedly different dietary nitrogen economy between the two groups. Conclusions: The findings suggest that distinct hepatic acceleration of urea synthesis may contribute to the protein loss seen in both myxedema and in thyrotoxicosis in humans.

Increased hepatic urea synthesis in patients with active inflammatory bowel disease

Background/Methods: Patients with active inflammatory bowel disease are often reported to be in negative nitrogen balance. Therefore, we examined basal and amino acid stimulated urea synthesis in 11 patients with active inflammatory bowel disease (six with Crohn's disease and five with ulcerative colitis) and in 10 patients with non-active disease (six with Crohn's disease and four with ulcerative colitis). A primed continuous infusion of an amino acid mixture was given from t=1 h to t=5 h; during the first and the last 2 h no amino acid infusion was given. Urea nitrogen synthesis rate was calculated in hourly intervals for 7 consecutive hours. Urea nitrogen synthesis rate was quantified independent of changes in blood amino acid concentration by means of the functional hepatic nitrogen clearance, i.e. the linear slope of the regression of urea nitrogen synthesis rate on blood amino acid concentration. Results: Basal urea nitrogen synthesis rate was 24.5±2.9 mmol/h in the patients with no disease activity and 43.8±2.2 mmol/h in patients with active disease ( p<0.01). During amino acid infusion urea nitrogen synthesis rate was elevated two-fold in the patients with active disease. Functional hepatic nitrogen clearance was 28.2±1.5 l/h in patients with no disease activity and 56.1±4.1 l/h in patients with active disease ( p<0.01). No differences between the two groups were observed as regards basal or stimulated plasma glucagon and cortisol and serum levels of interleukin-1α, interleukin-1β, tumor necrosis factor plasma and interleukin-6. Conclusions: The results show that the liver function related to conversion of amino-nitrogen to urea is increased in patients with active inflammatory bowel disease. No differences among known and possible regulators of urea synthesis were found between the two groups. The accelerated hepatic amino-nitrogen conversion contributes to the less efficient nitrogen economy in patients with active inflammatory bowel disease.

Somatostatin prevents the postoperative increases in plasma amino acid clearance and urea synthesis after elective cholecystectomy.

The importance of glucagon on postoperative changes in hepatic amino-nitrogen conversion were investigated in six patients undergoing elective cholecystectomy for uncomplicated gall stones. Patients were given infusions of somatostatin (bolus of 6 micrograms/kg followed by continuous infusion of 6 micrograms/kg/h) from induction of anaesthesia to the end of investigation, the first postoperative day (30 hours). Controls were 16 patients undergoing the same procedures omitting the somatostatin infusion. In all patients blood concentration and plasma clearance of total alpha-amino-nitrogen, and amino acid stimulated rate of urea synthesis were measured. Elective cholecystectomy decreased blood alpha-amino-nitrogen concentration from mean (SEM) 2.9 (0.2) to 2.4 (0.1) mmol/l (p < 0.05), increased the clearance of total alpha-amino-nitrogen from 5.2 (0.3) to 6.6 (0.3) ml/s (p < 0.05), and increased the rate of amino acid stimulated urea synthesis from 27 (1) to 37 (2) mumol/s (p < 0.05) pointing to increased hepatic removal of amino-nitrogen at expense of plasma amino-nitrogen. Infusion of somatostatin prevented increase of glucagon for 24 hours after surgery, and prevented the negative changes in postoperative nitrogen homeostasis resulting from the postoperative changes in hepatic nitrogen conversion, suggesting glucagon as mediator. The exact mechanism remains in doubt, however, because of the multiple effects of somatostatin.

Kinetics of hepatic amino-nitrogen conversion in ageing man.

Previous studies have shown that hepatic function, quantitatively measured by dynamic liver function tests, progressively declines with ageing. Urea synthesis is a specific process taking place in the liver; a reduced urea synthesis in response to a protein-rich metal has previously been demonstrated in the elderly, but the process has never been standardized in relation to amino acid supply. We measured the hepatic conversion of alpha-amino nitrogen into urea nitrogen in response to alanine infusion in 32 subjects, with normal routine liver and renal function tests and without evidence of previous hepatic disorders, belonging to three different age-groups (< or = 55 years, 56-70, > or = 71). The functional hepatic nitrogen clearance was reduced on average by 20% in subjects aged 56-70 years, and by 30% in subjects over 70 years old in comparison to the age-group under 55 years (ANOVA: P = 0.0001), and significantly correlated with age (r = -0.684). No sex differences were observed on the effects of age on hepatic clearance. Also, liver volume, measured by ultrasonography, was reduced with advancing age, but the age-related decrease in hepatic nitrogen conversion was not primarily dependent on decreased liver volume. The measurement of functional hepatic nitrogen clearance has already been validated as a quantitative liver function test in clinical hepatology. In keeping with previous studies, the age-related decline in hepatic nitrogen conversion points to a decreased functional capacity of the ageing hepatic parenchyma.

Hepatic conversion of amino-nitrogen to urea in thyroid diseases. II. A study in hyperthyroid patients

Conflicting data have been reported on the influence of thyroid hormones on hepatic nitrogen metabolism and on liver metabolic activity. We studied the urea-nitrogen synthesis rate (UNSR) and the kinetics of the process of hepatic amino-nitrogen to urea-nitrogen conversion in response to constant alanine infusion (ie, the functional hepatic nitrogen clearance [FHNC]) in five hyperthyroid female patients before and after the achievement of a stable euthyroid status. In the same patients, galactose elimination capacity and antipyrine clearance were also measured as quantitative indices of hepatic function. The basal urea synthesis rate was nearly doubled in hyperthyroid patients (35.6 ± 8.5 mol · h −1 v 17.6 ± 7.7 in euthyroid patients, P < .05) and increased linearly with increasing α-amino-nitrogen (α-AN) concentrations in both conditions. The urea synthesis rate during alanine infusion was still higher by approximately 30 mmol · h −1 in hyperthyroid subjects. The FHNC, calculated as the slope of the linear relation between the UNSR in each time interval and the corresponding average α-AN concentration, was not different (hyperthyroidism, 30.6 ± 7.2 L · h −1; euthyroidism, 28.5 ± 4.4; normal values > 25). The hepatic microsomal and cytosolic activities (antipyrine clearance and galactose elimination) were normal in hyperthyroid patients and did not change significantly after therapy. Our data show that the hepatic nitrogen metabolism of hyperthyroid patients is characterized by an upregulation of amino-nitrogen catabolism and loss of the sparing mechanism at low plasma amino acid levels, without any change in different metabolic activities.

Xylitol prevents glucagon induced increase in hepatic amino nitrogen conversion

Xylitol prevents glucagon induced increase in hepatic amino nitrogen conversion

Effects of glucose on hepatic conversion of aminonitrogen to urea in patients with cirrhosis: Relationship to glucagon

Glucose reduces the hepatic conversion of aminonitrogen to urea, quantified by the functional hepatic nitrogen clearance (i.e., the slope of the linear relation between urea synthesis rate and blood alpha-aminonitrogen concentration). This is due to a direct effect of glucose and to inhibition of glucagon. In this study, the effect of glucose on functional hepatic nitrogen clearance was examined during spontaneous hormone responses and during hormonal control by somatostatin. In 7 control subjects (study 1) and 9 patients with cirrhosis (study 2), functional hepatic nitrogen clearance was assessed twice in each subject: during infusion of alanine and during alanine administration superimposed on a continuous glucose infusion (blood glucose, on average = 8.4 mmol/L). In study 3, 6 patients with cirrhosis had functional hepatic nitrogen clearance determined on three occasions: during infusions of alanine and of alanine superimposed on infusion of somatostatin with either euglycemia or hyperglycemia (blood glucose = 8.4 mmol/L). In the control subjects (study 1), functional hepatic nitrogen clearance was 32.5 +/- 1.9 L/hr, and glucose reduced it to 18.4 +/- 0.9 L/hr (p < 0.01). In the cirrhotic patients, functional hepatic nitrogen clearance was only 9.8 +/- 1.3 L/hr (p < 0.01 vs. controls), and glucose did not change it. In the control subjects, glucose reduced the glucagon response to alanine from 204 +/- 36 ng/L to 106 +/- 8 ng/L (p < 0.05). In the cirrhotic patients the mean fasting glucagon level was increased twofold (180 +/- 21 ng/L). The response to alanine increased to 968 +/- 265 ng/L; it was not reduced by glucose. In study 3, somatostatin and hyperglycemia reduced functional hepatic nitrogen clearance from 13.2 +/- 1.5 L/hr to 6.4 +/- 0.7 L/hr (p < 0.01). Somatostatin and euglycemia reduced functional hepatic nitrogen clearance to 9.2 +/- 1.2 L/hr (p < 0.01 vs. alanine and hyperglycemia). The results show that the reduction by glucose of hepatic aminonitrogen conversion is lost in cirrhotic patients. The markedly increased glucagon response to alanine was not suppressed by glucose. Inhibition of the glucagon response by somatostatin reestablished the glucose effect, which was in part due to inhibition of glucagon in itself. Thus hepatic aminonitrogen conversion in cirrhosis depends on increased glucagon levels. The hormone-independent effect of glucose is preserved if the hyperglucagonemia is abolished, but the spontaneous high glucagon level overrules the glucose effect. The results indicate reduced hepatic contribution to the nitrogen-sparing effect of glucose in cirrhotic patients.

Effects of glucose on hepatic conversion of aminonitrogen to urea in patients with cirrhosis: Relationship to glucagon

Effects of glucose on hepatic conversion of aminonitrogen to urea in patients with cirrhosis: Relationship to glucagon

Effects of insulin and glucose on urea synthesis in normal man, independent of pancreatic hormone secretion

We investigated the inhibitory effect of insulin and glucose on hepatic amino- to urea-nitrogen conversion independent of endogenous insulin and glucagon secretion. Alanine-stimulated urea synthesis kinetics, as quantified by functional hepatic nitrogen clearance, i.e. the slope of the linear relation between blood alpha-amino nitrogen concentration and urea synthesis rate, were measured four times in each of six healthy volunteers, namely during spontaneous hormone responses, and during hormonal control by somatostatin and maintenance of basal hormone levels and euglycaemia, hyperinsulinaemia (85 +/- 8 mU/l), or hyperglycaemia (8.4 +/- 0.5 mmol/l). Hormonal control and euglycaemia reduced functional hepatic nitrogen clearance (mean +/- SD) by two-thirds (from 32.9 +/- 5.2 l/h to 12.2 +/- 3.4 l/h, p < 0.01). Hyperinsulinaemia did not change this (13.2 +/- 2.8 l/h), whereas hyperglycaemia further reduced functional hepatic nitrogen clearance by 40% to 7.4 +/- 1.3 l/h (p < 0.01). The reduction by hormonal control and euglycaemia is attributable to the abolition of the glucagon response to alanine infusion, as glucagon is known to up-regulate functional hepatic nitrogen clearance. Insulin did not regulate hepatic amino- to urea-nitrogen conversion, implying that the effect of insulin on urea production is due to its effect on blood amino acid supply to the liver. In contrast, glucose in itself reduced hepatic amino nitrogen conversion, independent of the hormonal responses to glucose. This means that the hepatic component of the amino-N-sparing effect of glucose depends on hyperglycaemia but not on hyperinsulinaemia.

Hepatic conversion of amino nitrogen to urea nitrogen in hypothyroid patients and upon l-thyroxine therapy

Conflicting studies have been reported regarding the influence of thyroid hormones on hepatic nitrogen metabolism and liver metabolic activity. We studied urea N synthesis rate (UNSR), functional hepatic N clearance (FHNC), galactose elimination capacity, and antipyrine clearance in six hypothyroid female patients before and after achievement of a stable euthyroid status. In both conditions, UNSR measured at intervals in response to constant alanine infusion was linearly related to the average α-amino N concentrations. In the hypothyroid state, peak UNSR was decreased by 31% in comparison with values measured in euthyroidism, which were in the normal range. FHNC (ie, the slope of the linear relation between UNSR and blood α-amino N concentration) is a measure of the kinetics of the process of hepatic amino N to urea N conversion; it was 19.8 ± 4.0 L · h −1 in hypothyroid patients and increased to normal values after l-thyroxine replacement (30.4 ± 3.3 L · h −1, P < .01; normal values > 25 L · h −1). Hepatic microsomal and cytosolic activities (antipyrine clearance and galactose elimination) were normal in hypothyroid patients and did not change significantly after therapy. Our data show a specific defect in hepatic handling of amino acids in hypothyroid patients, leading to reduced α-amino N to urea N conversion, in the absence of any detectable impairment in different hepatic metabolic activities.

Xylitol normalizes the accelerated hepatic capacity for conversion of amino nitrogen to urea nitrogen in diabetic rats.

In diabetes, the capacity of urea nitrogen synthesis, ie, a substrate-independent measure of the hepatic conversion of amino nitrogen to urea nitrogen, is increased. Xylitol decreases urea synthesis in normal rats. Capacity of urea nitrogen synthesis and nitrogen balance were measured during intravenous alanine loading in control rats, rats with experimental diabetes (streptozocin 75 mg/kg), and rats with experimental diabetes infused with xylitol to 1 mmol/L. In control rats, capacity of urea nitrogen synthesis was 9.4 +/- 1.1 mumol/min per 100 g of body weight, and nitrogen balance -2.7 +/- 1.2 mumol/min per 100 g of body weight. In the diabetics, these values were markedly increased to 26.6 +/- 1.9 and -16.3 +/- 2.1 mumol/min per 100 g of body weight, respectively (p < 0.01). The infusion of xylitol normalized these values to 11.2 +/- 1.0 and -3.6 +/- 2.1 mumol/min per 100 g of body weight for capacity of urea nitrogen synthesis and nitrogen balance, respectively. Xylitol did not change glucagon or insulin. Xylitol improved the nitrogen economy of uncontrolled diabetic rats by decreasing urea synthesis. The mechanism is not settled, but it does not involve insulin or glucagon.

Blockade of glucocorticoid receptors prevents the increase in urea synthesis after hysterectomy in rats

The postoperative increase in hepatic conversion of amino nitrogen to urea nitrogen seems to be a primary cause of post-surgical catabolism. The importance of glucocorticosteroids for the spontaneous urea nitrogen synthesis rate (UNSR) and for the maximally amino acid-stimulated capacity of urea nitrogen synthesis (CUNS) was investigated 3 and 24 h postoperatively, respectively, in hysterectomized rats. Corticosteroid effects were neutralized by glucocorticoid receptor blockade by the pharmacological analogue RU486. Hysterectomy doubled UNSR from 3.16 +/- 0.20 to 6.12 +/- 0.27 mumol (per min per 100 g body weight) after 3 h (P less than 0.01) and increased CUNS by 40% from 7.47 +/- 0.30 to 10.29 +/- 0.41 mumol (per min per 100 g body weight) after 24 h (P less than 0.01). These changes were both normalized by the receptor blockade. Hysterectomy decreased total blood alpha-amino nitrogen concentration by 25% from 3.4 +/- 0.2 to 2.6 +/- 0.2 mmol l-1 (P less than 0.05) 3 h after surgery, which was normalized by glucocorticoid receptor blockade. Hysterectomized rats lost 10 +/- 1 g the first 24 h after surgery. The blockade reduced the weight loss to 6 +/- 1 g body weight (P less than 0.05) without changing food intake. The results indicate that glucocorticoid action plays a major role in the postoperative increase in hepatic amino nitrogen conversion.

Indomethacin prevents the increase in urea synthesis capacity and the weight loss after hysterectomy in rats

Prostaglandins have been suggested to be mediators of post-operative catabolism. Previous studies have shown that stimulation of urea synthesis contributes to post-operative nitrogen loss. The effect of prostaglandins on this hepatic function was assessed in hysterectomized rats on the first post-operative day by measurements of the Capacity of Urea-N Synthesis (CUNS) with and without indomethacin treatment. Hysterectomy increased CUNS by 1 3 and led to a weight loss of 10 g in one day. Indomethacin prevented the increase in CUNS and the post-operative weight loss in operated animals; it also decreased CUNS by 1 3 in control rats. Blood amino-nitrogen concentration of indomethacin treated hysterectomized rats was 1 3 lower than in untreated animals, indicating an even more marked effect of indomethacin on post-operative tissue amino-acid release than on CUNS. Indomethacin exerts a nitrogen sparing effect, possibly depending on normalization of both post-operative hepatic amino-nitrogen conversion and tissue proteolysis. This may be of clinical importance in controlling post-operative catabolism.

Increased hepatic amino nitrogen conversion after elective cholecystectomy in man

1. The effect of elective, uncomplicated cholecystectomy on plasma clearances of amino acids and on amino acid-stimulated urea synthesis was investigated in 10 patients, pre-operatively and on the first post-operative day, and compared with six controls treated identically apart from the surgery. 2. A mixture of amino acids was given as a prime-continuous infusion. Steady-state concentrations 75% higher than basal were attained and were maintained for 90 min. The clearances of amino acids were calculated as the ratios between amino acid infusion rate and the concentration. The urea synthesis rate was calculated as urinary excretion corrected for accumulation and intestinal loss. 3. After surgery the fasting plasma concentrations of alanine, arginine, glutamine plus glutamate, glycine, proline, lysine and threonine decreased by 20-30%, but were unchanged in the control group. The plasma clearance of alpha-amino nitrogen increased from 5.1 +/- 1.2 ml/s before surgery (mean +/- SD) to 6.1 +/- 1.1 ml/s (P less than 0.05, paired t-test) after surgery due to increased clearances of the above-mentioned amino acids. In the control group, the clearance decreased from 6.4 +/- 1.6 to 5.9 +/- 1.1 (P less than 0.05, paired t-test). The amino acid-stimulated urea synthesis rate after surgery was 37 +/- 9 mumol of N/s vs 30 +/- 6 (P less than 0.01, paired t-test) in the controls despite a lower alpha-amino nitrogen concentration (4.5 +/- 0.5 mmol/l vs 5.1 +/- 0.5 mmol/l, P less than 0.05, paired t-test). The post-operative urea synthesis rate exceeded the amino nitrogen infusion by 20%.(ABSTRACT TRUNCATED AT 250 WORDS)