{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:38:55Z","timestamp":1791923935567,"version":"4.3.4"},"reference-count":32,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2017,5,11]],"date-time":"2017-05-11T00:00:00Z","timestamp":1494460800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aldosterone is a uniquely terrestrial hormone, first appearing in lungfish, which have both gills and lungs. Mineralocorticoid receptors (MRs), on the other hand, evolved much earlier, and are found in cartilaginous and bony fish, presumptive ligand cortisol. MRs have equivalent high affinity for aldosterone, progesterone, and cortisol; in epithelia, despite much higher cortisol circulating levels, aldosterone selectively activates MRs by co-expression of the enzyme 11\u03b2-hydroxysteroid dehydrogenase, Type 11. In tissues in which the enzyme is not expressed, MRs are overwhelmingly occupied but not activated by cortisol, which normally thus acts as an MR antagonist; in tissue damage, however, cortisol mimics aldosterone and acts as an MR agonist. The risk profile for primary aldosteronism (PA) is much higher than that in age-, sex-, and blood pressure-matched essential hypertensives. High levels of aldosterone per se are not the problem: in chronic sodium deficiency, as seen in the monsoon season in the highlands of New Guinea, plasma aldosterone levels are extraordinarily high, but cause neither hypertension nor cardiovascular damage. Such damage occurs when aldosterone levels are out of the normal feedback control, and are inappropriately elevated for the salt status of the individual (or experimental animal). The question thus remains of how excess salt can synergize with elevated aldosterone levels to produce deleterious cardiovascular effects. One possible mechanism is through the agency of the elusive ouabain-like factors (OLFs). Such factors are secreted from the adrenal in response to ACTH (adrenalocortical tropic hormone), to angiotensin via AT2R, and\u2014the polar opposite of aldosterone\u2014to sodium loading. They act on blood vessels to cause vasoconstriction and thus elevate blood pressure to dump excess sodium through pressure natriuresis. Their levels are chronically elevated in PA in response to the continually elevated sodium status, and they thus act to constrict coronary and systemic arteries. In the context of the elevated blood volume and total body sodium in a PA patient, this raises blood pressure and acts as the proximate cause of cardiovascular damage. If this is the case, it would appear to offer new insights into therapy for PA. One would be the use of digibindin, or its more recent successors as antagonists of OLFs acting on Na\/K ATPase at the vessel wall. A second would be to routinely combine a low dose MR antagonist, an ENaC inhibitor, and sodium restriction as first-line therapy for bilateral aldosterone overproduction. Finally, for unilateral cases post-surgery, there is good reason to include low-dose MRs in drug therapy if required, given the ability of cortisol in damaged blood vessels to mimic aldosterone vasoconstrictor action.<\/jats:p>","DOI":"10.3390\/ijms18051032","type":"journal-article","created":{"date-parts":[[2017,5,11]],"date-time":"2017-05-11T11:06:46Z","timestamp":1494500806000},"page":"1032","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":151,"title":["Aldosterone and Mineralocorticoid Receptors\u2014Physiology and Pathophysiology"],"prefix":"10.3390","volume":"18","author":[{"given":"John","family":"Funder","sequence":"first","affiliation":[{"name":"Hudson Institute of Medical Research, 27\u201331 Wright St, Clayton 3168, Victoria, Australia"},{"name":"Monash University, Clayton 3800, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1210\/endo-50-2-150","article-title":"A quantitative method for the bioassay of the effect of adrenal cortical steroids on mineral metabolism","volume":"50","author":"Simpson","year":"1952","journal-title":"Endocrinology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/0022-4731(72)90052-0","article-title":"Specific aldosterone binding in rat kidney and parotid","volume":"3","author":"Funder","year":"1972","journal-title":"J. Steroid Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1210\/en.2010-1444","article-title":"Mineralocorticoid receptors: Evolutionary and pathophysiological considerations","volume":"152","author":"Kassahn","year":"2011","journal-title":"Endocrinology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1210\/jcem-34-6-1039","article-title":"Plasma Deoxycorticosterone levels in man, with simultaneous measurements of aldosterone, corticosterone, cortisol and 11-Deoxycortisol","volume":"34","author":"Oddie","year":"1972","journal-title":"J. Clin. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6056","DOI":"10.1073\/pnas.80.19.6056","article-title":"Renal mineralocorticoid receptors and hippocampal corticosterone-binding species have identical intrinsic steroid specificity","volume":"80","author":"Krozowski","year":"1983","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1210\/jcem-51-5-1085","article-title":"Deoxycorticosterone and aldosterone clearance and binding in normal and hypertensive man","volume":"51","author":"Zipser","year":"1980","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/cen.12705","article-title":"Should aldosterone suppression tests be conducted during a particular phase of the menstrual cycle, and, if so, which phase? Results of a preliminary study","volume":"83","author":"Ahmed","year":"2015","journal-title":"Clin. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1126\/science.289.5476.119","article-title":"Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy","volume":"289","author":"Geller","year":"2000","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9202","DOI":"10.1073\/pnas.1633591100","article-title":"Differential binding of NAD+ and NADH allows the transcriptional corepressor carboxyl-terminal binding protein to serve as a metabolic sensor","volume":"100","author":"Fjeld","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.cmet.2013.10.005","article-title":"Mineralocorticoid receptor phosphorylation regulates ligand binding and renal response to volume depletion and hyperkalemia","volume":"18","author":"Shibata","year":"2013","journal-title":"Cell Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.cmet.2013.10.010","article-title":"Angiotensin retains sodium by dephosphorylating mineralocorticoid receptors in renal intercalated cells","volume":"18","author":"Funder","year":"2013","journal-title":"Cell Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/sj.bjp.0706220","article-title":"Genomic and nongenomic effects of aldosterone in the rat heart: Why is spironolactone cardioprotective?","volume":"145","author":"Chai","year":"2005","journal-title":"Br. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1161\/HYPERTENSIONAHA.109.136242","article-title":"Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction","volume":"54","author":"Mihailidou","year":"2009","journal-title":"Hypertension"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1056\/NEJM199909023411001","article-title":"The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators","volume":"341","author":"Pitt","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1016\/j.jacc.2005.01.015","article-title":"Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism","volume":"45","author":"Milliez","year":"2005","journal-title":"JACC"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5070","DOI":"10.1210\/jc.2005-0681","article-title":"Evidence for abnormal left ventricular structure and function in normotensive individuals with familial hyperaldosteronism type I","volume":"90","author":"Stowasser","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"H273","DOI":"10.1152\/ajpheart.00183.2008","article-title":"ACTH-induced hypertension is dependent on the ouabain-binding site of the \u03b12-Na+-K+-ATPase subunit","volume":"295","author":"Lorenz","year":"2008","journal-title":"AJP Heart Circ. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.1210\/jc.2015-1268","article-title":"Stress-induced aldosterone hyper-secretion in a substantial subset of patients with essential hypertension","volume":"100","author":"Markou","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1161\/01.HYP.29.1.401","article-title":"Angiotensin II stimulates secretion of endogenous ouabain from bovine adrenocortical cells via angiotensin type 2 receptors","volume":"29","author":"Laredo","year":"1997","journal-title":"Hypertension"},{"key":"ref_20","first-page":"419","article-title":"Increase in plasma ouabainlike inhibitor of Na+, K+-ATPase with high sodium intake in patients with essential hypertension","volume":"3","author":"Hasegawa","year":"1987","journal-title":"J. Clin. Hypertens."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15845","DOI":"10.1073\/pnas.0507358102","article-title":"The highly conserved cardiac glycoside binding site of Na, K-ATPase plays a role in blood pressure regulation","volume":"102","author":"Lorenz","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1161\/01.HYP.6.3.425","article-title":"Direct action of aldosterone on transmembrane 22Na efflux from arterial smooth muscle. Rapid and delayed effects","volume":"6","author":"Moura","year":"1984","journal-title":"Hypertension"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0009-9120(87)80109-1","article-title":"The role of arterial mineralocorticoid receptors in the mechanism of hypertension: Findings and hypothesis","volume":"20","author":"Kornel","year":"1987","journal-title":"Clin. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1111\/j.1476-5381.2012.02194.x","article-title":"Aldosterone affects blood flow and vascular tone regulated by endothelium-derived NO: Therapeutic implications","volume":"168","author":"Toda","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1111\/j.1365-2362.2011.02531.x","article-title":"High prevalence of autonomous aldosterone secretion among patients with essential hypertension","volume":"41","author":"Gouli","year":"2011","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1210\/jc.2012-3353","article-title":"Evidence of primary aldosteronism in a predominantly female cohort of normotensive individuals: A very high odds ratio for progression into arterial hypertension","volume":"98","author":"Markou","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1161\/HYPERTENSIONAHA.116.08952","article-title":"A continuum of autonomous aldosterone secretion in normotension","volume":"69","author":"Baudrand","year":"2017","journal-title":"Hypertension"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2736","DOI":"10.1210\/jc.2003-032149","article-title":"Distinguishing the antihypertensive and electrolyte effects of eplerenone","volume":"89","author":"Levy","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3153","DOI":"10.1210\/en.2004-0005","article-title":"Eplerenone, but not steroid withdrawal, reverses cardiac fibrosis in deoxycorticosterone\/salt-treated rats","volume":"145","author":"Young","year":"2004","journal-title":"Endocrinology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3623","DOI":"10.1210\/en.2005-1527","article-title":"Mineralocorticoid receptor blockade but not steroid withdrawal reverses renal fibrosis in deoxycorticosterone\/salt rats","volume":"147","author":"Lam","year":"2006","journal-title":"Endocrinology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"R529","DOI":"10.1152\/ajpregu.00518.2005","article-title":"Rostafuroxin: An ouabain antagonist that corrects renal and vascular Na+-K+-ATPase alterations in ouabain and adducin-dependent hypertension","volume":"290","author":"Ferrari","year":"2006","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1124\/jpet.114.217133","article-title":"Rostafuroxin protects from podocyte injury and proteinuria induced by adducin genetic variants and ouabain","volume":"351","author":"Ferrandi","year":"2014","journal-title":"J. Pharmacol. Exp. 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