{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T07:43:46Z","timestamp":1775634226214,"version":"3.50.1"},"reference-count":58,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2018,11,6]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      8\u2010Aminoguanosine and 8\u2010aminoguanine are K\n                      <jats:sup>+<\/jats:sup>\n                      \u2010sparing natriuretics that increase glucose excretion. Most effects of 8\u2010aminoguanosine are due to its metabolism to 8\u2010aminoguanine. However, the mechanism by which 8\u2010aminoguanine affects renal function is unknown and is the focus of this investigation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Because 8\u2010aminoguanine has structural similarities with inhibitors of the epithelial sodium channel (ENaC), Na\n                      <jats:sup>+<\/jats:sup>\n                      \/H\n                      <jats:sup>+<\/jats:sup>\n                      exchangers, and adenosine A\n                      <jats:sub>1<\/jats:sub>\n                      receptors, we examined the effects of 8\u2010aminoguanine on\n                      <jats:styled-content style=\"fixed-case\">EN<\/jats:styled-content>\n                      aC activity in mouse collecting duct cells, on intracellular\n                      <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content>\n                      of human proximal tubular epithelial cells, on responses to a selective A\n                      <jats:sub>1<\/jats:sub>\n                      \u2010receptor agonist in\u00a0vivo, and on renal excretory function in A\n                      <jats:sub>1<\/jats:sub>\n                      \u2010receptor knockout rats. These experiments showed that 8\u2010aminoguanine did not block\n                      <jats:styled-content style=\"fixed-case\">EN<\/jats:styled-content>\n                      aC, Na\n                      <jats:sup>+<\/jats:sup>\n                      \/H\n                      <jats:sup>+<\/jats:sup>\n                      exchangers, or A\n                      <jats:sub>1<\/jats:sub>\n                      receptors. Because Rac1 enhances activity of mineralocorticoid receptors and some guanosine analogues inhibit Rac1, we examined the effects of 8\u2010aminoguanine on Rac1 activity in mouse collecting duct cells. Rac1 activity was significantly inhibited by 8\u2010aminoguanine. Because in\u00a0vitro 8\u2010aminoguanine is a purine nucleoside phosphorylase (\n                      <jats:styled-content style=\"fixed-case\">PNP<\/jats:styled-content>\n                      ase) inhibitor, we examined the effects of a natriuretic dose of 8\u2010aminoguanine on urinary excretion of\n                      <jats:styled-content style=\"fixed-case\">PNP<\/jats:styled-content>\n                      ase substrates and products. 8\u2010Aminoguanine increased and decreased, respectively, urinary excretion of\n                      <jats:styled-content style=\"fixed-case\">PNP<\/jats:styled-content>\n                      ase substrates and products. Next we compared in rats the renal effects of intravenous doses of 9\u2010deazaguanine (\n                      <jats:styled-content style=\"fixed-case\">PNP<\/jats:styled-content>\n                      ase inhibitor) versus 8\u2010aminoguanine. 8\u2010Aminoguanine and 9\u2010deazaguanine induced similar increases in urinary Na\n                      <jats:sup>+<\/jats:sup>\n                      and glucose excretion, yet only 8\u2010aminoguanine reduced K\n                      <jats:sup>+<\/jats:sup>\n                      excretion. Nsc23766 (Rac1 inhibitor) mimicked the effects of 8\u2010aminoguanine on K\n                      <jats:sup>+<\/jats:sup>\n                      excretion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      8\u2010Aminoguanine increases Na\n                      <jats:sup>+<\/jats:sup>\n                      and glucose excretion by blocking\n                      <jats:styled-content style=\"fixed-case\">PNP<\/jats:styled-content>\n                      ase and decreases K\n                      <jats:sup>+<\/jats:sup>\n                      excretion by inhibiting Rac1.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.118.010085","type":"journal-article","created":{"date-parts":[[2018,10,25]],"date-time":"2018-10-25T05:02:20Z","timestamp":1540443740000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["8\u2010Aminoguanine Induces Diuresis, Natriuresis, and Glucosuria by Inhibiting Purine Nucleoside Phosphorylase and Reduces Potassium Excretion by Inhibiting Rac1"],"prefix":"10.1161","volume":"7","author":[{"given":"Edwin K.","family":"Jackson","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Chemical Biology University of Pittsburgh School of Medicine Pittsburgh PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zaichuan","family":"Mi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology University of Pittsburgh School of Medicine Pittsburgh PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas R.","family":"Kleyman","sequence":"additional","affiliation":[{"name":"Renal\u2010Electrolyte Division Department of Medicine University of Pittsburgh School of Medicine Pittsburgh PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongmei","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology University of Pittsburgh School of Medicine Pittsburgh PA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2006.8.1033"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1006\/niox.1997.0143"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(95)01281-6"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M313904200"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0235623100"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.8.3375"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.12.4533"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2012.03.004"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/tx00033a004"},{"key":"e_1_3_1_11_2","first-page":"63","article-title":"A rat model of purine nucleoside phosphorylase deficiency","volume":"59","author":"Osborne WR","year":"1986","unstructured":"Osborne WR, Barton RW. 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