Urea Nitrogen Synthesis Rate Research Articles

Glucagon increases hepatic efficacy for urea synthesis

The effect of glucagon on the relation between urea synthesis and blood amino acid concentration was studied in seven healthy volunteers. Alanine was given as prime-continuous infusions and, after 1 hr for equilibration, the urea nitrogen synthesis rate was measured in two periods of about 2 hrs as urinary excretion corrected for accumulation and intestinal hydrolysis. During one of the periods, glucagon was infused to obtain a constant concentration of 200–1200 ng/l. The spontaneous urea synthesis during the alanine infusion was 86–141 mmol/hr and linearly related to the alanine concentrations of 1.33–2.99 mmol/l. The hepatic clearance of alanine-nitrogen to urea-nitrogen, assessed by the ratio between the increase in the urea synthesis rate and alanine concentration, was 23 ± 4 l/hr (mean ± S.D.). Glucagon increased the rate of urea synthesis by 35 ± 11 mmol/hr ( p < 0.02) and decreased the alanine concentration by 0.22 ± 0.06 mmol/1 ( p < 0.01). Glucagon increased the hepatic nitrogen clearance to an average of 42 ± 13 l/hr ( p < 0.01). The difference between infusion of amino-nitrogen and appearance of urea-nitrogen was +15 ± 10 mmol/hr during alanine infusion alone and −11 ± 25 mmol/hr during exogenous glucagon. The loss of nitrogen could be accounted for by depletion of non-alanine amino acids from the blood. Glucagon increases the efficacy of urea synthesis, which may be of importance for catabolism by changing the hepatic contribution to nitrogen homeostasis.

Loss of nitrogen from organs in rats induced by exogenous glucagon.

Rats weighing 220 g were injected sc with zinc protamin glucagon 20 micrograms once daily (recurrent hyperglucagonemia) and zinc protamin glucagon 60 micrograms three times daily (chronic hyperglucagonemia); the controls received the vehicle three times daily. In the first group blood glucagon rose to above 200 ng/liter for 5 h every day; in the second group it constantly stayed above 600 ng/liter. After both 2 (n = 5) and 14 (n = 5) days treatment the control total blood alpha-amino-nitrogen (AAN) concentration was 4.3 +/- 0.1 mmol/liter, and the urea nitrogen synthesis rate was 4.9 +/- 0.4 mumol/(min.100 g BW) (mean +/- SEM) in controls. In recurrent hyperglucagonemic rats, treated for both 2 (n = 5) and 14 (n = 5) days, total AAN was 3.6 +/- 0.2 mmol/liter (P less than 0.05 vs. control) and urea nitrogen synthesis rate 4.5 +/- 0.8 mumol/(min.100 g BW). In chronic hyperglucagonemic, treated for both 2 (n = 5) and 14 (n = 5) days, total AAN was 2.2 +/- 0.1 mmol/liter (P less than 0.05 vs. control) and UNSR 7.9 +/- 0.8 mumol/(min.100g BW) (P less than 0.05 vs. control). The urea excretion was identical in controls and during recurrent hyperglucagonemia, but it was increased by 50% during chronic hyperglucagonemia. Food intake was the same in all groups. N Balances decreased from 10 mmol/24 h to 5 mmol/24 h (P less than 0.05) by chronic hyperglucagonemia. The total organ N content did not change by recurrent hyperglucagonemia, but in chronic hyperglucagonemia it decreased to 65-85% (P less than 0.01) in carcass, intestines, liver, and kidneys. In conclusion chronic but not recurrent hyperglucagonemia increases the rate of urea synthesis and decreases the blood amino acid concentration. This is suggested to be a reason for the loss of N from organs by chronic hyperglucagonemia.

Plasma clearances of branched-chain amino acids in control subjects and in patients with cirrhosis

In an attempt to clarify the pathogenesis of the decreased branched-chain amino acid (BCAA) plasma concentrations in cirrhosis, the plasma clearances were measured in 7 patients with cirrhosis and in 7 age- and sex-matched control subjects. BCAA were given as prime-continuous infusions. The plasma clearances of valine, isoleucine, and leucine, calculated as infusion rate divided by steady state concentration, were low normal in cirrhotics despite hyperinsulinaemia, but different BCAA had different clearances (P less than 0.01). The endogenous basal appearance rates of BCAA, estimated by the basal concentrations multiplied by the plasma clearances, were lower in cirrhotics (P less than 0.025). The apparent theoretical volumes of distribution of BCAA, assessed by the ratio between the clearance and the concentration decay constant after infusion stop, were on average 67% of the total body weight, and were neither different among the three BCAA, nor between the two groups. The urea nitrogen synthesis rate did not increase significantly, suggesting that most of the infused BCAA nitrogen was taken up in peripheral tissues. The decreased concentration of BCAA in cirrhotics (394 +/- 81 mumol/l (mean +/- SD) in the present series vs 510 +/- 68 in controls; P less than 0.025) is not attributable to changes in plasma clearance. The most likely explanation is decreased afflux of BCAA into plasma.

Increased intestinal hydrolysis of urea in patients with alcoholic cirrhosis.

Fourteen patients with biopsy-proven alcoholic liver cirrhosis in a clinically stable phase but with compromised liver function entered the study, together with 10 control persons. All had normal creatinine clearance, and none received antibiotics or hormones. They ingested a diet containing 1 g of protein/kg body weight daily during the study. The fractional intestinal loss of newly synthesized urea, determined by a 14C-urea tracer method, was increased from 0.17 +/- 0.08 in controls to 0.26 +/- 0.08 in cirrhotics (mean +/- SD, P less than 0.02). Urea nitrogen synthesis rate, determined as urinary excretion rate, corrected for accumulation in the total body water and for fractional intestinal loss, was the same in controls and cirrhotics (26.1 +/- 3.8 and 22.1 +/- 6.8 mmol/h, respectively). The patients with cirrhosis had a significantly greater nitrogen balance than the control group (12.5 +/- 7.0 mmol/h versus 7.0 +/- 5.9 mmol/h; P less than 0.05). Furthermore, there was a positive correlation between intestinal loss and blood urea nitrogen concentration (r = 0.68, P less than 0.01) in patients with cirrhosis but not in controls. The increased endogenous ammonia load of cirrhotics corresponds to an extra protein intake of 30-35 g/day. In patients with cirrhosis prophylactic treatment with, for example, lactulose is rational before reduction in dietary protein.

Synthesis of urea after stimulation with amino acids: relation to liver function.

Hepatic urea synthesis is the organism's main channel for the disposal of nitrogen and it may be an 'essential' liver function. In six control subjects and five patients with cirrhosis of the liver urea synthesis was studied during continuous infusion for six to 24 hours of about 3 mmol alpha-amino nitrogen/h X kg body weight. The urea synthesis rate was calculated in intervals of two hours as urinary excretion with correction for accumulation in the total body water and for hydrolysis of urea in the gut. The peripheral venous plasma alpha-amino nitrogen concentration increased from 3 to about 14 mmol/l and the urea nitrogen synthesis rate from 25 to about 215 mmol/h. In all cases the urea synthesis rate rose linearly with the alpha-amino concentration throughout the examined range. The slope of this linear relationship is an expression of the hepatic conversion of alpha-amino nitrogen to urea nitrogen ('functional hepatic nitrogen clearance'). The functional hepatic nitrogen clearance was 22.4 l/h in control subjects and 13.7 1/h (P < 0.025) in the patients with cirrhosis. It was correlated with quantitative measures of the liver function (the galactose elimination capacity, r = 0.84, and the clearance of antipyrine, 4 = 0.80). These observations, while confirming the abundant capacity of the urea synthesis system, imply that a given urea synthesis rate requires a higher alpha-amino level in patients with reduced liver function.