{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T21:28:43Z","timestamp":1761514123645,"version":"3.41.0"},"reference-count":71,"publisher":"American Physiological Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Renal Physiology"],"published-print":{"date-parts":[[2000,5,1]]},"abstract":"<jats:p>The mechanism by which chlorpropamide (CP) treatment promotes antidiuresis is unknown. CP competitively inhibited antidiuretic hormone (ADH) binding and adenylyl cyclase (AC) stimulation (inhibition constants K<jats:sub>i<\/jats:sub>and K\u2032<jats:sub>i<\/jats:sub>of 2.8 mM and 250 \u03bcM, respectively) in the LLC-PK<jats:sub>1<\/jats:sub>cell line. CP (333 \u03bcM) increased the apparent K<jats:sub>a<\/jats:sub>of ADH for AC activation (0.31 vs. 0.08 nM) without affecting a maximal response, suggesting competitive antagonism. Because CP lowers \u201cbasal\u201d AC activity and the AC activation-ADH receptor occupancy relationship (A-O plots), it is an ADH inverse agonist. Twenty-four-hour CP exposure (100 \u03bcM) upregulated the ADH receptors without affecting affinity. This lowered K<jats:sub>a<\/jats:sub>and increased basal AC activity and maximal response (1.86 vs. 1.35 and 14.9 vs. 10.6 fmol cAMP \u22c5 min<jats:sup>\u2212<\/jats:sup><jats:sup>1<\/jats:sup>\u22c5 10<jats:sup>3<\/jats:sup>cells<jats:sup>\u2212<\/jats:sup><jats:sup>1<\/jats:sup>, n = 6, P &lt; 0.05). NaCl, which potentiates ADH stimulation, also increased basal AC activity. This, together with the CP-ADH inverse agonism and increased basal AC activity at higher receptor density, unmasks constitutive receptor signaling. The CP-ADH inverse agonism explains receptor upregulation and predicts the need for residual ADH with functional isoreceptors for CP-mediated antidiuresis. This could be why CP ameliorates partial central diabetes insipidus but not nephrogenic diabetes insipidus.<\/jats:p>","DOI":"10.1152\/ajprenal.2000.278.5.f799","type":"journal-article","created":{"date-parts":[[2017,12,23]],"date-time":"2017-12-23T12:47:32Z","timestamp":1514033252000},"page":"F799-F808","source":"Crossref","is-referenced-by-count":15,"title":["Chlorpropamide upregulates antidiuretic hormone receptors and unmasks constitutive receptor signaling"],"prefix":"10.1152","volume":"278","author":[{"given":"Jacques A.","family":"Durr","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Veterans Affairs Medical Center, Bay Pines 33744;"},{"name":"Department of Medicine, University of South Florida College of Medicine, Tampa 33612;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes","family":"Hensen","sequence":"additional","affiliation":[{"name":"Klinikum Hannover Nordstadt, Medizinische Klinik, Hannover 30167;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tobias","family":"Ehnis","sequence":"additional","affiliation":[{"name":"Department of Medicine IV, University of Erlangen-Nuernberg, Erlangen 8520, Germany; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary S.","family":"Blankenship","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"(With the Technical Assistance of C. Klein)","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-26-12-1325"},{"key":"B2","doi-asserted-by":"crossref","first-page":"11687","DOI":"10.1016\/S0021-9258(17)32625-X","volume":"69","author":"Barker EL","year":"1994","journal-title":"J Biol Chem"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1210\/endo-95-3-771"},{"key":"B4","doi-asserted-by":"crossref","first-page":"3238","DOI":"10.1016\/S0021-9258(17)40828-3","volume":"253","author":"Bergman R","year":"1978","journal-title":"J Biol Chem"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1210\/endo-86-5-1028"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116698"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/374214a0"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/374272a0"},{"key":"B10","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/S0022-3565(25)20399-8","volume":"258","author":"Caltabiano S","year":"1991","journal-title":"J Pharmacol Exp Ther"},{"key":"B11","doi-asserted-by":"crossref","first-page":"29557","DOI":"10.1016\/S0021-9258(18)43916-6","volume":"269","author":"Ceresa BP","year":"1994","journal-title":"J Biol Chem"},{"key":"B12","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/S0026-895X(25)10022-9","volume":"45","author":"Chidiac P","year":"1993","journal-title":"Mol Pharmacol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.19.7321"},{"key":"B14","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S0026-895X(25)08958-8","volume":"41","author":"Costa T","year":"1992","journal-title":"Mol Pharmacol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI109697"},{"key":"B17","first-page":"E97","volume":"235","author":"De Lean A","year":"1978","journal-title":"Am J Physiol Endocrinol Metab Gastrointest Physiol"},{"key":"B18","doi-asserted-by":"crossref","first-page":"7108","DOI":"10.1016\/S0021-9258(20)79672-9","volume":"255","author":"De Lean A","year":"1980","journal-title":"J Biol Chem"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1172\/JCI109241"},{"key":"B21","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1152\/ajplegacy.1972.222.3.657","volume":"222","author":"Dousa TP.","year":"1972","journal-title":"Am J Physiol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(70)90286-9"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.1993.265.5.E728"},{"key":"B24","doi-asserted-by":"crossref","first-page":"18453","DOI":"10.1016\/S0021-9258(19)36984-4","volume":"267","author":"Durr JA","year":"1992","journal-title":"J Biol Chem"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1982.tb37460.x"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.1981.240.4.F311"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-75-4-549"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.5.2587"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1959.tb39589.x"},{"key":"B31","doi-asserted-by":"crossref","first-page":"3219","DOI":"10.1016\/S0021-9258(17)40826-X","volume":"253","author":"Hechter O","year":"1978","journal-title":"J Biol Chem"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1530\/eje.0.1320459"},{"key":"B33","doi-asserted-by":"crossref","first-page":"21590","DOI":"10.1016\/S0021-9258(18)45781-X","volume":"65","author":"Horstman DA","year":"1990","journal-title":"J Biol Chem"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-29-5-738"},{"key":"B35","doi-asserted-by":"crossref","first-page":"6599","DOI":"10.1016\/S0021-9258(19)41108-3","volume":"250","author":"Johnson RA","year":"1975","journal-title":"J Biol Chem"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.16.7212"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.1988.254.2.F165"},{"key":"B38","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/S0026-895X(25)13182-9","volume":"44","author":"Kong H","year":"1993","journal-title":"Mol Pharmacol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111086"},{"key":"B40","doi-asserted-by":"crossref","first-page":"25970","DOI":"10.1016\/S0021-9258(18)47145-1","volume":"269","author":"Leeb-Lundberg LMF","year":"1994","journal-title":"J Biol Chem"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(00)88989-0"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/0165-6147(93)90048-O"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1210\/endo-102-3-785"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/357336a0"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-34-4-704"},{"key":"B46","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1016\/S0022-3565(25)24092-7","volume":"245","author":"Mah SC","year":"1988","journal-title":"J Pharmacol Exp Ther"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.1986.250.5.F802"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-30-4-488"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1210\/endo-86-5-1024"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(00)88963-4"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(98)01585-3"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1210\/endo-106-3-967"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1982.tb37464.x"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1210\/endo-111-6-2025"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(80)90515-1"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-36-1-174"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(89)90705-X"},{"key":"B58","doi-asserted-by":"crossref","first-page":"3211","DOI":"10.1016\/S0021-9258(17)40825-8","volume":"253","author":"Nakahara T","year":"1978","journal-title":"J Biol Chem"},{"key":"B59","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/S0026-895X(25)11081-X","volume":"39","author":"Neve KA","year":"1991","journal-title":"Mol Pharmacol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/0026-0495(81)90222-5"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.45.28318"},{"key":"B62","first-page":"767","volume":"7","author":"Quintana J","year":"1993","journal-title":"Mol Endocrinol"},{"key":"B63","doi-asserted-by":"crossref","first-page":"3415","DOI":"10.1016\/S0021-9258(19)69624-9","volume":"256","author":"Roy C","year":"1981","journal-title":"J Biol Chem"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1981.tb15463.x"},{"key":"B65","doi-asserted-by":"crossref","first-page":"3423","DOI":"10.1016\/S0021-9258(19)69625-0","volume":"256","author":"Roy C","year":"1981","journal-title":"J Biol Chem"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1977.tb11743.x"},{"key":"B67","doi-asserted-by":"crossref","first-page":"4625","DOI":"10.1016\/S0021-9258(18)53442-6","volume":"268","author":"Samama P","year":"1993","journal-title":"J Biol Chem"},{"key":"B68","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/S0026-895X(25)10009-6","volume":"45","author":"Samama P","year":"1994","journal-title":"Mol Pharmacol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb00726.x"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.3.808"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1016\/0165-6147(92)90116-N"},{"key":"B73","first-page":"165","volume":"13","author":"Skorecki KL","year":"1987","journal-title":"Miner Electrolyte Metab"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1120439"},{"key":"B75","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/S0026-895X(25)09836-0","volume":"46","author":"Westphal RS","year":"1994","journal-title":"Mol Pharmacol"},{"key":"B76","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1152\/ajplegacy.1971.221.3.911","volume":"221","author":"Zweig SM","year":"1971","journal-title":"Am J Physiol"}],"container-title":["American Journal of Physiology-Renal Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajprenal.2000.278.5.F799","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T04:36:44Z","timestamp":1751171804000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajprenal.2000.278.5.F799"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,5,1]]},"references-count":71,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2000,5,1]]}},"alternative-id":["10.1152\/ajprenal.2000.278.5.F799"],"URL":"https:\/\/doi.org\/10.1152\/ajprenal.2000.278.5.f799","relation":{},"ISSN":["1931-857X","1522-1466"],"issn-type":[{"type":"print","value":"1931-857X"},{"type":"electronic","value":"1522-1466"}],"subject":[],"published":{"date-parts":[[2000,5,1]]}}}