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Pathway Description
Eplerenone Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2020-08-10
Last Updated: 2023-10-25
Eplerenone is an oral drug used to treat conditions such as hypertension and congestive heart failure. Its main target is the collecting duct of the nephron.
In the principal cells of the collecting duct, sodium and water reabsorption occur, along with potassium excretion. The sodium channel (ENaC) transports Na+ from the tubule lumen into the principal cells, then the NA+/K+ ATPase pumps the Na+ into the interstitium where it reabsorbed into the blood. K+ ions are pumped into the principal cell from the interstitium via the Na+/K+ ATPase, then the K+ channel transports K+ from the cell into the lumen where it is excreted in urine. Water reabsorption is linked to Na+ reabsorption and occurs via the aquaporins.
Aldosterone is released from the adrenal cortex of the kidney and acts on the nephrons in the adrenal medulla. Aldosterone binds to mineralocorticoid receptors in the cytosol of the principal cells in the collecting duct. The mineralocorticoid receptors undergo dimerization and activation and move into the nucleus where they undergo transcription. Protein is then synthesized in the cytosol. This effect on gene transcription leads to an upregulation of sodium channels in the apical membrane and Na+/K+ ATPase in the basolateral membrane, aiding an increase in Na+ and water reabsorption and K+ excretion.
Eplerenone binds to the mineralocorticoid receptors in the cytosol and blocks aldosterone binding. This prevents the aldosterone effects on gene transcription, therefore, there is a decrease in Na+ channels and Na+/K+ ATPase in the membrane. Sodium reabsorption decreases, the concentration of Na+ in the lumen becomes high and as a result, water reabsorption also decreases. The effects on Na+/K+ ATPase results in reduced K+ excretion.
This effect of eplerenone is important for treating conditions like hypertension because the increased water excretion in urine leads to decreased blood plasma volume, lowering blood pressure.
Eplerenone may also have the same effect on Na+ and water reabsorption in the late distal convoluted tubule.
Side effects of taking eplerenone include hyperkalemia, hypertriglyceridemia, flu like symptoms, mastodynia, fatigue, abnormal vaginal bleeding, gynecomastia, headache, dizziness, diarrhea, abdominal pain, cough, angina, myocardial infarction.
References
Eplerenone Pathway References
Sam R, & Ives H.E., & Pearce D (2017). Diuretic agents. Katzung B.G.(Ed.), Basic & Clinical Pharmacology, 14e. McGraw-Hill. https://accessmedicine-mhmedical-com.login.ezproxy.library.ualberta.ca/content.aspx?bookid=2249§ionid=175217531
Ritter, James (2020). The kidney and the urinary system. Rang and Dale’s Pharmacology (9th ed). Retrieved from: https://www-clinicalkey-com.login.ezproxy.library.ualberta.ca/#!/browse/book/3-s2.0-C2016004202X
Wishart, D., Knox, C., Guo, A., Shrivastava, S., Hassanali, M., Stothard, P., . . . Woolsey, J. (2005, June). Eplerenone. Retrieved August 10th , 2020, from https://www.drugbank.ca/drugs/DB00700
Hughes JC, Cassagnol M. Eplerenone. [Updated 2020 Feb 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK553100/
Scott JH, Menouar MA, Dunn RJ. Physiology, Aldosterone. [Updated 2020 May 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470339/
Voilley N, Lingueglia E, Champigny G, Mattei MG, Waldmann R, Lazdunski M, Barbry P: The lung amiloride-sensitive Na+ channel: biophysical properties, pharmacology, ontogenesis, and molecular cloning. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):247-51. doi: 10.1073/pnas.91.1.247.
Pubmed: 8278374
McDonald FJ, Snyder PM, McCray PB Jr, Welsh MJ: Cloning, expression, and tissue distribution of a human amiloride-sensitive Na+ channel. Am J Physiol. 1994 Jun;266(6 Pt 1):L728-34. doi: 10.1152/ajplung.1994.266.6.L728.
Pubmed: 8023962
Ludwig M, Bolkenius U, Wickert L, Marynen P, Bidlingmaier F: Structural organisation of the gene encoding the alpha-subunit of the human amiloride-sensitive epithelial sodium channel. Hum Genet. 1998 May;102(5):576-81. doi: 10.1007/s004390050743.
Pubmed: 9654208
Voilley N, Bassilana F, Mignon C, Merscher S, Mattei MG, Carle GF, Lazdunski M, Barbry P: Cloning, chromosomal localization, and physical linkage of the beta and gamma subunits (SCNN1B and SCNN1G) of the human epithelial amiloride-sensitive sodium channel. Genomics. 1995 Aug 10;28(3):560-5. doi: 10.1006/geno.1995.1188.
Pubmed: 7490094
McDonald FJ, Price MP, Snyder PM, Welsh MJ: Cloning and expression of the beta- and gamma-subunits of the human epithelial sodium channel. Am J Physiol. 1995 May;268(5 Pt 1):C1157-63. doi: 10.1152/ajpcell.1995.268.5.C1157.
Pubmed: 7762608
Saxena A, Hanukoglu I, Strautnieks SS, Thompson RJ, Gardiner RM, Hanukoglu A: Gene structure of the human amiloride-sensitive epithelial sodium channel beta subunit. Biochem Biophys Res Commun. 1998 Nov 9;252(1):208-13. doi: 10.1006/bbrc.1998.9625.
Pubmed: 9813171
Waldmann R, Champigny G, Bassilana F, Voilley N, Lazdunski M: Molecular cloning and functional expression of a novel amiloride-sensitive Na+ channel. J Biol Chem. 1995 Nov 17;270(46):27411-4. doi: 10.1074/jbc.270.46.27411.
Pubmed: 7499195
Ji HL, Su XF, Kedar S, Li J, Barbry P, Smith PR, Matalon S, Benos DJ: Delta-subunit confers novel biophysical features to alpha beta gamma-human epithelial sodium channel (ENaC) via a physical interaction. J Biol Chem. 2006 Mar 24;281(12):8233-41. doi: 10.1074/jbc.M512293200. Epub 2006 Jan 19.
Pubmed: 16423824
Bangel-Ruland N, Sobczak K, Christmann T, Kentrup D, Langhorst H, Kusche-Vihrog K, Weber WM: Characterization of the epithelial sodium channel delta-subunit in human nasal epithelium. Am J Respir Cell Mol Biol. 2010 Apr;42(4):498-505. doi: 10.1165/rcmb.2009-0053OC. Epub 2009 Jun 11.
Pubmed: 19520916
Saxena A, Hanukoglu I, Saxena D, Thompson RJ, Gardiner RM, Hanukoglu A: Novel mutations responsible for autosomal recessive multisystem pseudohypoaldosteronism and sequence variants in epithelial sodium channel alpha-, beta-, and gamma-subunit genes. J Clin Endocrinol Metab. 2002 Jul;87(7):3344-50. doi: 10.1210/jcem.87.7.8674.
Pubmed: 12107247
Mulders SM, Knoers NV, Van Lieburg AF, Monnens LA, Leumann E, Wuhl E, Schober E, Rijss JP, Van Os CH, Deen PM: New mutations in the AQP2 gene in nephrogenic diabetes insipidus resulting in functional but misrouted water channels. J Am Soc Nephrol. 1997 Feb;8(2):242-8.
Pubmed: 9048343
de Mattia F, Savelkoul PJ, Bichet DG, Kamsteeg EJ, Konings IB, Marr N, Arthus MF, Lonergan M, van Os CH, van der Sluijs P, Robertson G, Deen PM: A novel mechanism in recessive nephrogenic diabetes insipidus: wild-type aquaporin-2 rescues the apical membrane expression of intracellularly retained AQP2-P262L. Hum Mol Genet. 2004 Dec 15;13(24):3045-56. doi: 10.1093/hmg/ddh339. Epub 2004 Oct 27.
Pubmed: 15509592
de Mattia F, Savelkoul PJ, Kamsteeg EJ, Konings IB, van der Sluijs P, Mallmann R, Oksche A, Deen PM: Lack of arginine vasopressin-induced phosphorylation of aquaporin-2 mutant AQP2-R254L explains dominant nephrogenic diabetes insipidus. J Am Soc Nephrol. 2005 Oct;16(10):2872-80. doi: 10.1681/ASN.2005010104. Epub 2005 Aug 24.
Pubmed: 16120822
Roudier N, Ripoche P, Gane P, Le Pennec PY, Daniels G, Cartron JP, Bailly P: AQP3 deficiency in humans and the molecular basis of a novel blood group system, GIL. J Biol Chem. 2002 Nov 29;277(48):45854-9. doi: 10.1074/jbc.M208999200. Epub 2002 Sep 17.
Pubmed: 12239222
Ishibashi K, Sasaki S, Saito F, Ikeuchi T, Marumo F: Structure and chromosomal localization of a human water channel (AQP3) gene. Genomics. 1995 May 20;27(2):352-4. doi: 10.1006/geno.1995.1055.
Pubmed: 7558005
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Kawakami K, Ohta T, Nojima H, Nagano K: Primary structure of the alpha-subunit of human Na,K-ATPase deduced from cDNA sequence. J Biochem. 1986 Aug;100(2):389-97. doi: 10.1093/oxfordjournals.jbchem.a121726.
Pubmed: 2430951
Ruiz A, Bhat SP, Bok D: Characterization and quantification of full-length and truncated Na,K-ATPase alpha 1 and beta 1 RNA transcripts expressed in human retinal pigment epithelium. Gene. 1995 Apr 3;155(2):179-84. doi: 10.1016/0378-1119(94)00812-7.
Pubmed: 7536695
Vanmolkot KR, Kors EE, Hottenga JJ, Terwindt GM, Haan J, Hoefnagels WA, Black DF, Sandkuijl LA, Frants RR, Ferrari MD, van den Maagdenberg AM: Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. Ann Neurol. 2003 Sep;54(3):360-6. doi: 10.1002/ana.10674.
Pubmed: 12953268
De Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L, Ballabio A, Aridon P, Casari G: Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet. 2003 Feb;33(2):192-6. doi: 10.1038/ng1081. Epub 2003 Jan 21.
Pubmed: 12539047
Swoboda KJ, Kanavakis E, Xaidara A, Johnson JE, Leppert MF, Schlesinger-Massart MB, Ptacek LJ, Silver K, Youroukos S: Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. Ann Neurol. 2004 Jun;55(6):884-7. doi: 10.1002/ana.20134.
Pubmed: 15174025
Heinzen EL, Swoboda KJ, Hitomi Y, Gurrieri F, Nicole S, de Vries B, Tiziano FD, Fontaine B, Walley NM, Heavin S, Panagiotakaki E, Fiori S, Abiusi E, Di Pietro L, Sweney MT, Newcomb TM, Viollet L, Huff C, Jorde LB, Reyna SP, Murphy KJ, Shianna KV, Gumbs CE, Little L, Silver K, Ptacek LJ, Haan J, Ferrari MD, Bye AM, Herkes GK, Whitelaw CM, Webb D, Lynch BJ, Uldall P, King MD, Scheffer IE, Neri G, Arzimanoglou A, van den Maagdenberg AM, Sisodiya SM, Mikati MA, Goldstein DB: De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet. 2012 Sep;44(9):1030-4. doi: 10.1038/ng.2358. Epub 2012 Jul 29.
Pubmed: 22842232
Ishii A, Saito Y, Mitsui J, Ishiura H, Yoshimura J, Arai H, Yamashita S, Kimura S, Oguni H, Morishita S, Tsuji S, Sasaki M, Hirose S: Identification of ATP1A3 mutations by exome sequencing as the cause of alternating hemiplegia of childhood in Japanese patients. PLoS One. 2013;8(2):e56120. doi: 10.1371/journal.pone.0056120. Epub 2013 Feb 8.
Pubmed: 23409136
Demos MK, van Karnebeek CD, Ross CJ, Adam S, Shen Y, Zhan SH, Shyr C, Horvath G, Suri M, Fryer A, Jones SJ, Friedman JM: A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis. 2014 Jan 28;9:15. doi: 10.1186/1750-1172-9-15.
Pubmed: 24468074
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