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Potassium deficiency decreases the capacity for urea synthesis and markedly increases ammonia in rats

Mikkelsen, ACD; Thomsen, KL; Vilstrup, H; Aamann, L; Jones, H; Mookerjee, RP; Hamilton-Dutoit, S; ... Aagaard, NK; + view all (2021) Potassium deficiency decreases the capacity for urea synthesis and markedly increases ammonia in rats. American Journal of Physiology - Gastrointestinal and Liver Physiology , 320 (4) G474-G483. 10.1152/ajpgi.00136.2020. Green open access

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Abstract

Our study provides novel findings of experimental hypokalemia reducing urea cycle functionality and thereby severely increasing plasma ammonia. This is pathophysiologically interesting because plasma ammonia increases during hypokalemia by a hitherto unknown mechanism, which may be particular important in relation to the unexplained link between hypokalemia and hepatic encephalopathy. Potassium deficiency decreases gene expression, protein synthesis, and growth. The urea cycle maintains body nitrogen homeostasis including removal of toxic ammonia. Hyperammonemia is an obligatory trait of liver failure, increasing the risk for hepatic encephalopathy, and hypokalemia is reported to increase ammonia. We aimed to clarify the effects of experimental hypokalemia on the in vivo capacity of the urea cycle, on the genes of the enzymes involved, and on ammonia concentrations. Female Wistar rats were fed a potassium-free diet for 13 days. Half of the rats were then potassium repleted. Both groups were compared with pair- and free-fed controls. The following were measured: in vivo capacity of urea-nitrogen synthesis (CUNS); gene expression (mRNA) of urea cycle enzymes; plasma potassium, sodium, and ammonia; intracellular potassium, sodium, and magnesium in liver, kidney, and muscle tissues; and liver sodium/potassium pumps. Liver histology was assessed. The diet induced hypokalemia of 1.9 ± 0.4 mmol/L. Compared with pair-fed controls, the in vivo CUNS was reduced by 34% (P < 0.01), gene expression of argininosuccinate synthetase 1 (ASS1) was decreased by 33% (P < 0.05), and plasma ammonia concentrations were eightfold elevated (P < 0.001). Kidney and muscle tissue potassium contents were markedly decreased but unchanged in liver tissue. Protein expressions of liver sodium/potassium pumps were unchanged. Repletion of potassium reverted all the changes. Hypokalemia decreased the capacity for urea synthesis via gene effects. The intervention led to marked hyperammonemia, quantitatively explainable by the compromised urea cycle. Our findings motivate clinical studies of patients with liver disease.

Type: Article
Title: Potassium deficiency decreases the capacity for urea synthesis and markedly increases ammonia in rats
Open access status: An open access version is available from UCL Discovery
DOI: 10.1152/ajpgi.00136.2020
Publisher version: https://doi.org/10.1152/ajpgi.00136.2020
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Gastroenterology & Hepatology, Physiology, hyperammonemia, potassium deficiency, urea synthesis, rats, NA,K-ACTIVATED ADENOSINE-TRIPHOSPHATASE, LOW EXTERNAL K+, PROTEIN-SYNTHESIS, IN-VIVO, HEPATIC-ENCEPHALOPATHY, RENAL AMMONIAGENESIS, ARTERIAL AMMONIA, SKELETAL-MUSCLE, GROWTH-HORMONE, CYCLE ENZYMES
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > MAPS Faculty Office
URI: https://discovery.ucl.ac.uk/id/eprint/10139445
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