{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T05:11:31Z","timestamp":1781759491993,"version":"3.54.5"},"reference-count":46,"publisher":"American Physiological Society","issue":"4","funder":[{"DOI":"10.13039\/501100003035","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF17OC0026342"],"award-info":[{"award-number":["NNF17OC0026342"]}],"id":[{"id":"10.13039\/501100003035","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003035","name":"Aase og Ejnar Danielsens Fond","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003035","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.physiology.org"],"crossmark-restriction":true},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2021,4,1]]},"abstract":"<jats:p> 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\u2009days. 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\u2009\u00b1\u20090.4\u2009mmol\/L. Compared with pair-fed controls, the in vivo CUNS was reduced by 34% ( P &lt; 0.01), gene expression of argininosuccinate synthetase 1 ( ASS1) was decreased by 33% ( P &lt; 0.05), and plasma ammonia concentrations were eightfold elevated ( P &lt; 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. <\/jats:p>","DOI":"10.1152\/ajpgi.00136.2020","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T15:31:03Z","timestamp":1609947063000},"page":"G474-G483","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Potassium deficiency decreases the capacity for urea synthesis and markedly increases ammonia in rats"],"prefix":"10.1152","volume":"320","author":[{"given":"Anne Catrine D.","family":"Mikkelsen","sequence":"first","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen Louise","family":"Thomsen","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark"},{"name":"UCL Institute of Liver and Digestive Health, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik","family":"Vilstrup","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luise","family":"Aamann","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Jones","sequence":"additional","affiliation":[{"name":"UCL Institute of Liver and Digestive Health, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajeshwar P.","family":"Mookerjee","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark"},{"name":"UCL Institute of Liver and Digestive Health, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Hamilton-Dutoit","sequence":"additional","affiliation":[{"name":"Department of Pathology, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Frystyk","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels Kristian","family":"Aagaard","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1445-5994.2009.02146.x"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1136\/pgmj.62.725.187"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/101.2.273"},{"key":"B4","first-page":"1","volume":"618","author":"D\u00f8rup I","year":"1994","journal-title":"Acta Physiol Scand Suppl"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1079\/BJN19890029"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.plaphy.2016.06.009"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI104761"},{"key":"B8","first-page":"208","volume":"82","author":"Ching S","year":"1973","journal-title":"J Lab Clin Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/j.1478-3231.2010.02302.x"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00010.2011"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-196645060-00011"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1991.274"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1136\/gut.21.11.990"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1079\/095442299108728857"},{"key":"B15","first-page":"1170","volume":"61","author":"Gaduputi V","year":"2014","journal-title":"Hepatogastroenterology"},{"key":"B16","first-page":"362","volume":"19","author":"Zavagli G","year":"1993","journal-title":"Miner Electrolyte Metab"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1478-3231.2010.02362.x"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0676.1988.tb00992.x"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)40885-4"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/0168-8278(90)90072-y"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/s0168-8278(86)80058-7"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3109\/00365518509161013"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.13.2.156"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-609106-9.50014-2"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1081\/JDI-100104718"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1053\/jren.2002.33511"},{"key":"B27","first-page":"287","volume":"82","author":"Gustafson AB","year":"1973","journal-title":"J Lab Clin Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510250429"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1172\/JCI104039"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00333.2007"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.10311013"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1042\/CS20010027"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1172\/JCI108813"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1152\/ajplegacy.1939.127.2.385"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1470253"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.1984.tb07488.x"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)68456-X"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.87.4.591"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1988.255.2.C252"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00588.2001"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2016.00057"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21838"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510290309"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21180"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.jceh.2018.08.001"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(02)01477-8"}],"container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/ajpgi.00136.2020","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T08:59:52Z","timestamp":1624438792000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.physiology.org\/doi\/10.1152\/ajpgi.00136.2020"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,1]]},"references-count":46,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,4,1]]}},"alternative-id":["10.1152\/ajpgi.00136.2020"],"URL":"https:\/\/doi.org\/10.1152\/ajpgi.00136.2020","relation":{},"ISSN":["0193-1857","1522-1547"],"issn-type":[{"value":"0193-1857","type":"print"},{"value":"1522-1547","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,1]]},"assertion":[{"value":"2020-04-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-12-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-04-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}