The mineralocorticoid receptor (MR) is expressed in many cell types throughout the body, including specific neurons, and mediates diverse functions, many of which are just now being appreciated. MR that pertain to the central modulation of cardiovascular function and health are addressed herein.

Addison described patients with adrenal cortical destruction as having ‘asthenic’ hearts over 150 years ago. A century later deoxycorticosterone became the first effective treatment of Addison disease [1]; however, it was soon recognized that overzealous replacement led to hypertension and renal damage [2] and that it increased vascular responses to epinephrine and norepinephrine in healthy people [3]. Within a few years aldosterone, the primary mineralocorticoid, was isolated [4], and primary aldosteronism (Conn’s syndrome) was described as associated with refractory hypertension and hypokalemia leading to heart and kidney failure [5]. Notwithstanding early evidence of cardiovascular effects [3,6,7] occurring before the appearance of hypertension, the retention of sodium and water by the kidneys [8] became commonly accepted as solely responsible for the hypertension produced by mineralocorticoid + salt excess.

The demonstration of specific binding of aldosterone in select areas of the brain, as well as the heart and vessels [9], and the finding that the ablation of the anteroventral area of the third ventricle abrogated mineralocorticoid + salt, renovascular and Dahl salt-sensitive (SS) rat hypertension [for a review, see [10]] kindled interest in the central hemodynamic effects of mineralocorticoids. Selective infusions of mineralocorticoid receptor (MR) agonists and antagonists in various animal models of hypertension confirmed that MR of the circumventricular organs were crucial for the development of several models of hypertension and that activation of MR in the amygdala increased salt appetite [for a review, see [11]].

Patients with primary aldosteronism have cardiac hypertrophy compared to patients with essential hypertension who have similar levels of hypertension for the same duration [12,13]. Studies in experimental animals suggested that the inflammation leading to fibrosis and hypertrophy of the heart, vessels and kidneys associated with systemic mineralocorticoid + salt excess were mediated by MR in these tissues independently of significant increases in blood pressure [14,15,16,17]. The assumption that ‘end organ’ pathology is totally independent of hypertension has been contested [18]. MR are prominently expressed in the macrophages, important components of the inflammatory response that migrate into tissue and produce inflammatory cytokines soon after injury, as well as before any other pathology is noted when an animal is exposed to mineralocorticoid + salt excess [17,19,20,21]. MR in the paraventricular nuclei are also involved in the increased proinflammatory cytokines in the blood and heart associated with cardiac ischemia and heart failure in the rat, as well as in the augmented neuronal activity in the paraventricular nuclei leading to increased sympathetic drive to the heart [22,23,24]. MR in the forebrain are crucial to survival of the acute phase of cardiac ischemia induced by coronary ligation in the rat; however, their continued, excessive and/or inappropriate activation exacerbates and accelerates the progression of heart failure due to inappropriate sympathetic nerve activity, volume retention and inflammation despite peripheral blockade of the renin-angiotensin-aldosterone system [25].

The MR is a member of the steroid nuclear receptor superfamily, ligand-activated transcription factors that include the glucocorticoid receptors (GR) with which the MR shares some homology. In addition to promoting the transcription of cell-specific genes, the MR also initiates nongenomic effects through second-messenger pathways. MR bind aldosterone, corticosterone and cortisol with similar affinity [26], yet aldosterone activates the MR in target cells such as transport epithelia of the distal nephron and colon, despite basal circulating levels of glucocorticoids that are 100–1,000 times greater than normal values for aldosterone. There is only one MR gene; the splice variants so far described do not account for tissue-specific differences in MR ligand activation specificity [27,28]. MR specificity for aldosterone in epithelial mineralocorticoid target tissues is conferred by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) that inactivates cortisol and corticosterone, thus allowing access to aldosterone [29]. In the absence of 11β-HSD2, MR in the kidney tubular epithelia are activated by the more abundant glucocorticoids, producing the same effects as activation by an excess of aldosterone: inappropriate Na+ and water retention, K+ and H+ excretion, and hypertension [30]. Expression of 11β-HSD2 in the brain is limited and restricted to a few circumventricular nuclei and select neurons of the nucleus tractus solitarii [31,32,33,34]. The highest concentrations of MR in the hippocampus, where they are not coexpressed with 11β-HSD2, thus are bound primarily by glucocorticoids [35,36,37].

Notwithstanding limited 11β-HSD2 expression in the brain, in vitro incubation of rat brain minces with tritiated corticosterone indicates that it is efficiently converted to the inactive steroid 11-dehydrocorticosterone [38,39]. Moreover, intracerebroventricular infusions of 11β-HSD inhibitors produces hypertension, and the intracerebroventricular infusion of an MR antagonist abrogates the hypertension produced by the systemic administration of these inhibitors [11,40,41]. Though there is evidence for another hydroxysteroid dehydrogenase, none has been isolated or cloned [42,43,44].

11β-HSD inhibitors block both 11β-HSD types 1 and 2. 11β-HSD1 is a hydroxysteroid dehydrogenase like 11β-HSD2 in the absence of hexose-6-phosphate dehydrogenase to regenerate NADPH, its obligate cofactor for reductase activity [45,46]. Few neurons were found to express 11β-HSD1, and most of these, with the exception of small neurons adjacent to Purkinje cells and a few neurons in brainstem nuclei, also expressed hexose-6-phosphate dehydrogenase [47].

Neurosteroids are produced in the CNS from cholesterol or circulating precursors where they probably serve autocrine and paracrine functions [48]. We speculated that synthesis of aldosterone in cells expressing the MR would give aldosterone a stoichiometric advantage over glucocorticoids in the absence of 11β-HSD2. All the requisite components for aldosterone synthesis from cholesterol have been documented in the rat and human brain [39,49,50,51,52]. Minced brain parts from intact and adrenalectomized rats synthesize aldosterone and precursors from endogenous as well as tritiated substrates, with similar efficiency [39]. The aldosterone content of the brain reflects that of the plasma in intact rats on diets of different salt content [53]. Aldosterone concentrations in brains of adrenalectomized rats are low but consistently measurable and significantly higher than that of their plasma, which is usually below the limits of detection. These data suggest that extra-adrenal aldosterone synthesis does occur in the brain, but that most of the aldosterone in the brain derives from the adrenal gland [53]. The relevance of local aldosterone synthesis has yet to be proven; however, the Dahl SS rat may offer some insight.

Salt-induced hypertension in the Dahl SS rat is prevented by the central infusion of an MR antagonist and by ablation of the anteroventral area of the third ventricle, a maneuver that prevents mineralocorticoid-salt hypertension, even though circulating aldosterone in Dahl SS rats is normal or low [54]. The hypertension is also mitigated by the central infusion of an inhibitor of the aldosterone synthase enzyme 19-ethynyl deoxycorticosterone [38] and subseizure doses of trilostane, a 3β-hydroxysteroid dehydrogenase inhibitor [55]. These findings suggest that excessive or unregulated aldosterone production within the brain is part of the complex pathogenesis of hypertension in the Dahl SS rat.

If extra-adrenally produced aldosterone is relevant for homeostasis, it must also be regulated. Adrenal aldosterone production is tightly regulated, primarily by angiotensin II [56] which increases the expression of aldosterone synthase [57]. The renin-angiotensin system (RAS) of the hypothalamus, but not the brainstem, appears to be regulated by sodium status in a manner similar to that of the systemic RAS [58]; however, expression of aldosterone synthase mRNA in the brain was not found to be altered by sodium depletion in a different study [59]. As the aldosterone production by the adrenal gland far exceeds that by the brain even when maximally suppressed by a chronic high salt diet, it has been impossible to accurately measure the effect of sodium consumption on the extra-adrenal production of aldosterone [53]. The central infusion of angiotensin-converting enzyme inhibitors and angiotensin receptor and MR inhibitors, but not blockade of the systemic RAS or MR, was reported to decrease sympathetic drive and increase tissue and circulating inflammatory cytokines produced by coronary ligation [23,60]. While not conclusive, these data suggest that synthesis of aldosterone within the brain may be regulated by a local RAS.

Unlike MR of transport epithelia, the consequences of activation of MR in different parts of the brain and heart differ depending on the MR ligand [36,61]. Aldosterone, but not corticosterone, activates MR in circumventricular areas associated with blood pressure control to increase blood pressure [62]. Aldosterone replacement in the adrenalectomized animal does not restore normal corticosterone-mediated functions of the hippocampal MR, including modulation of arousal and stress responses and some forms of memory and cognitive functions [35,36,37].

The area of study with perhaps the greatest potential of finding mechanisms for both ligand- and cell-specific functions of the MR is the differential distribution of proteins that interact with steroid receptors. Chaperone proteins, coactivators and corepressors, underlie diversity and cell specificity of other steroid-receptor-mediated signals; however, little is known about the transcriptional modulation of the MR. The ligand-binding conformation of the MR monomer is stabilized by binding to several cell-type-specific chaperone proteins, including heat shock protein 90. These may alter the binding affinity for aldosterone compared to the glucocorticoids in some cells. Upon binding to a ligand, the MR sheds the chaperone proteins and dimerizes either as a homo- or heterodimer with the GR in the nucleus, before or at the time it binds to hormone response elements in the promoter regions of specific genes, increasing the expression of these genes by recruiting requisite transcriptional machinery [63,64,65,66,67]. MR and GR are coexpressed in many cells of the brain, including cerebellar Purkinje and hippocampal pyramidal cells [49,68], and heterodimerization of MR and GR appears to be important in the transcriptional regulation of glucocorticoid-responsive genes in the brain [69,70]. Whether GR and MR heterodimerization figures in the control of blood pressure and neurohumoral control of inflammation is another important area of study.

Transcription efficiency is modulated by coactivators or corepressors, proteins that bind activated receptors. To date, there are no cofactors or hormone response elements known to be specific for the MR; however, mRNA of two steroid receptor coactivator (SRC) protein family members, SRC-la and SRC-le, has been reported in specific areas of the brain. Expression of SRC-1a mRNA was greater in the arcuate, paraventricular and ventromedial nuclei of the hypothalamus, the locus coeruleus and the trigeminal motor nucleus, as well as the anterior pituitary [71], areas associated with blood pressure homeostasis as well as mineralocorticoid hypertension. It is plausible that cell-specific protein interactions with the MR alter its ligand specificity or transcriptional efficiency.

Experimental evidence that the inappropriate activation of MR by mineralocorticoids in specific areas of the brain and heart participates in the pathogenesis of several forms of hypertension and exacerbates end organ failure led to a renewed interest in the role of aldosterone and MR in heart failure and to several clinical studies that demonstrated that MR antagonists clearly and significantly ameliorate symptoms and outcomes of patients with severe congestive heart failure or who are at risk of cardiac or renal failure [72,73,74]. Use of MR antagonists in such patients has now become the standard of care. The salutary effects may be due to blocking MR in the heart, vessels, macrophages and/or cardiovascular centers in the brain; however, what effects MR antagonists at these relatively low therapeutic doses may have on hippocampal mediated functions, most of which are unrelated to cardiovascular homeostasis, is unknown. It is critical that more be learned about the basic biology and function of the MR in the various areas of the brain to guide the development of more specific therapeutic agents.

This work has been supported by medical research funds from the Department of Veterans Affairs and a National Institutes of Health grant (HL 27737, HL 075321-01, HL 27255-22).

Anderson E, Kinsell LW, et al: The treatment of Addison’s disease by the intraoral administration of desoxycorticosterone acetate tablets. J Clin Endocrinol Metab 1949;9:1324–1332.
Luft R, Sjögren B: The effect of desoxycorticosterone acetate and sodium chloride on blood pressure and renal function. Acta Endocrinol (Copenh) 1949;3:56–70.
Raab W, Humphreys RJ, Lepeschkin E: Potentiation of pressor effects of norepinephrine and epinephrine in man by desoxycorticosterone acetate. J Clin Invest 1950;29:1397–1404.
Tait JF, Tait SAS: A steroid memoir: a decade (or more) of electrocortin (aldosterone). Steroids 1988;51:213–250.
Conn JW: Primary aldosteronism, a new clinical syndrome. J Lab Clin Med 1955;45:3–7.
Vanatta JC, Cottle KE: Effect of desoxycorticosterone acetate on the peripheral vascular reactivity of dogs. Am J Physiol 1955;151:119–122.
Jones AW, Hart RG: Altered ion transport in aortic smooth muscle during deoxycorticosterone acetate hypertension in rats. Circ Res 1975;37:333–341.
Kuhlman D, Ragan C, Ferrebee JW, Atchley DW, Loeb RF: Toxic effects of deoxycorticosterone esters in dogs. Science 1939;90:496–497.
Birmingham MK, Stumpf WE, Sar M: Nuclear localization of aldosterone in rat brain cells assessed by autoradiography. Experientia 1979;35:1240–1241.
Brody MJ, Varner KJ, Vasquez EC, Lewis SJ: Central nervous system and the pathogenesis of hypertension: sites and mechanisms. Hypertension 1991;18:III7–III12.
Gomez-Sanchez EP: Central hypertensive effects of aldosterone. Front Neuroendocrinol 1997;18:440–462.
Tanabe A, Naruse M, Naruse K, Hase M, Yoshimoto T, Tanaka M, Seki T, Demura H: Left ventricular hypertrophy is more prominent in patients with primary aldosteronism than in patients with other types of secondary hypertension. Hypertens Res 1997;20:85–90.
Rossi GP, Sacchetto A, Pavan E, Scognamiglio R, Pietra M, Pessina AC: Left ventricular systolic function in primary aldosteronism and hypertension. J Hypertens 1998;16:2075–2077.
Gomez-Sanchez EP: Brain mineralocorticoid receptors: orchestrators of hypertension and end-organ disease. Curr Opin Nephrol Hypertens 2004;13:191–196.
Gomez-Sanchez EP: Mineralocorticoid modulation of central control of blood pressure. Steroids 1995;60:69–72.
Young MJ, Funder JW: Aldosterone and the heart. Trends Endocrinol Metab 2000;11:224–226.
Rocha R, Rudolph AE, Frierdich GE, Nachowiak DA, Kekec BK, Blomme EA, McMahon EG, Delyani JA: Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol 2002;283:H1802–H1810.
Kurtz TW: False claims of blood pressure-independent protection by blockade of the renin angiotensin aldosterone system? Hypertension 2003;41:193–196.
Quinkler M, Zehnder D, Eardley KS, Lepenies J, Howie AJ, Hughes SV, Cockwell P, Hewison M, Stewart PM: Increased expression of mineralocorticoid effector mechanisms in kidney biopsies of patients with heavy proteinuria. Circulation 2005;112:1435–1443.
Young MJ, Moussa L, Dilley R, Funder JW: Early inflammatory responses in experimental cardiac hypertrophy and fibrosis: effects of 11 beta-hydroxysteroid dehydrogenase inactivation. Endocrinology 2003;144:1121–1125.
Keidar S, Kaplan M, Pavlotzky E, Coleman R, Hayek T, Hamoud S, Aviram M: Aldosterone administration to mice stimulates macrophage NADPH oxidase and increases atherosclerosis development: a possible role for angiotensin-converting enzyme and the receptors for angiotensin II and aldosterone. Circulation 2004;109:2213–2220.
Francis J, Weiss RM, Johnson AK, Felder RB: Central mineralocorticoid receptor blockade decreases plasma TNF-alpha after coronary artery ligation in rats. Am J Physiol Regul Integr Comp Physiol 2003;284:R328–R335.
Francis J, Weiss RM, Wei SG, Johnson AK, Beltz TG, Zimmerman K, Felder RB: Central mineralocorticoid receptor blockade improves volume regulation and reduces sympathetic drive in heart failure. Am J Physiol Heart Circ Physiol 2001;281:H2241–H2251.
Francis GS: Aldosterone inhibition and heart failure: too good to be true? Am Heart J 2001;141:1–2.
Felder RB, Francis J, Zhang ZH, Wei SG, Weiss RM, Johnson AK: Heart failure and the brain: new perspectives. Am J Physiol Regul Integr Comp Physiol 2003;284:R259–R276.
Arriza JW, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, Evans RM: Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science 1987;237:268–275.
Zennaro MC, Farman N, Bonvalet JP, Lombes M: Tissue-specific expression of alpha and beta messenger ribonucleic acid isoforms of the human mineralocorticoid receptor in normal and pathological states. J Clin Endocrinol Metab 1997;82:1345–1352.
Zhou MY, Gomez-Sanchez CE, Gomez-Sanchez EP: An alternatively spliced mineralocorticoid receptor mRNA causing truncation of the steroid binding domain. Mol Cell Endocrinol 2000;159:125–131.
Funder JW, Pearce PT, Smith R, Smith AI: Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science 1988;242:583–585.
White PC: 11beta-hydroxysteroid dehydrogenase and its role in the syndrome of apparent mineralocorticoid excess. Am J Med Sci 2001;322:308–315.
Roland BL, Li KX, Funder JW: Hybridization histochemical localization of 11 beta-hydroxysteroid dehydrogenase type 2 in rat brain. Endocrinology 1995;136:4697–4700.
Geerling JC, Kawata M, Loewy AD: Aldosterone-sensitive neurons in the rat central nervous system. J Comp Neurol 2006;494:515–527.
Geerling JC, Engeland WC, Kawata M, Loewy AD: Aldosterone target neurons in the nucleus tractus solitarius drive sodium appetite. J Neurosci 2006;26:411–417.
Geerling JC, Loewy AD: Aldosterone-sensitive neurons in the nucleus of the solitary tract: bidirectional connections with the central nucleus of the amygdala. J Comp Neurol 2006;497:646–657.
Wrange O, Yu ZY: Mineralocorticoid receptor in rat kidney and hippocampus: characterization and quantitation by isoelectric focusing. Endocrinology 1983;113:243–250.
De Kloet ER, Van Acker SA, Sibug RM, Oitzl MS, Meijer OC, Rahmouni K, de Jong W: Brain mineralocorticoid receptors and centrally regulated functions. Kidney Int 2000;57:1329–1336.
Engelmann M, Landgraf R, Lorscher P, Conzelmann C, Probst JC, Holsboer F, Reul JM: Downregulation of brain mineralocorticoid and glucocorticoid receptor by antisense oligodeoxynucleotide treatment fails to alter spatial navigation in rats. Eur J Pharmacol 1998;361:17–26.
Gomez-Sanchez CE, Zhou MY, Cozza EN, Morita H, Eddleman FC, Gomez-Sanchez EP: Corticosteroid synthesis in the central nervous system. Endocr Res 1996;22:463–470.
Gomez-Sanchez CE, Zhou MY, Cozza EN, Morita H, Foecking MF, Gomez-Sanchez EP: Aldosterone biosynthesis in the rat brain. Endocrinology 1997;138:3369–3373.
Gomez-Sanchez EP, Gomez-Sanchez CE: Central hypertensinogenic effects of glycyrrhizic acid and carbenoxolone. Am J Physiol 1992;263:E1125–E1130.
Gomez-Sanchez EP, Gomez-Sanchez CE: Maternal hypertension and progeny blood pressure: role of aldosterone and 11b-HSD. Hypertension 1999;33:1369–1373.
Low SC, Assaad SN, Rajan V, Chapman KE, Edwards CRW, Seckl JR: Regulation of 11b-hydroxysteroid dehydrogenase by sex steroids in vivo: further evidence for the existence of a second dehydrogenase in rat kidney. J Endocrinol 1993;139:27–35.
Gomez-Sanchez EP, Ganjam V, Chen YJ, Cox DL, Zhou MY, Thanigaraj S, Gomez-Sanchez CE: The sheep kidney contains a novel unidirectional, high affinity NADP+-dependent 11b-hydroxysteroid dehydrogenase (11-HSD3). Steroids 1997;62:444–450.
Gomez-Sanchez EP, Gomez-Sanchez CE: First there was one, then two... why more 11b-hydroxysteroid dehydrogenases? Endocrinology 1997;138:5087–5088.
Banhegyi G, Benedetti A, Fulceri R, Senesi S: Cooperativity between 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase in the lumen of the endoplasmic reticulum. J Biol Chem 2004;279:27017–27021.
Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM: 11β-Hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev 2004;25:831–866.
Gomez-Sanchez EP, Romero DG, de Rodriguez AF, Warden MP, Krozowski Z, Gomez-Sanchez CE: Hexose-6-phosphate dehydrogenase and 11β-hydroxysteroid dehydrogenase-1 tissue distribution in the rat. Endocrinology 2008;149:525–533.
Le Goascogne C, Robel P, Gouézou M, Sananes N, Baulieu E, Waterman M: Neurosteroids: cytochrome P-450scc in rat brain. Science 1987;237:1212–1215.
MacKenzie SM, Clark CJ, Fraser R, Gomez-Sanchez CE, Connell JMC, Davies E: Expression of 11b-hydroxylase and aldosterone synthase genes in rat brain. J Mol Endocrinol 2000;24:321–328.
Gomez-Sanchez EP, Gomez-Sanchez CE: Is aldosterone synthesized in the CNS regulated and functional? Trends Endocrinol Metab 2003;14:444–446.
King SR, Manna PR, Ishii T, Syapin PJ, Ginsberg SD, Wilson K, Walsh LP, Parker KL, Stocco DM, Smith RG, Lamb DJ: An essential component in steroid synthesis, the steroidogenic acute regulatory protein, is expressed in discrete regions of the brain. J Neurosci 2002;22:10613–10620.
Yu L, Romero DG, Gomez-Sanchez CE, Gomez-Sanchez EP: Steroidogenic enzyme gene expression in the human brain. Mol Cell Endocrinol 2002;190:9–17.
Gomez-Sanchez EP, Ahmad N, Romero DG, Gomez-Sanchez CE: Is aldosterone synthesized within the rat brain? Am J Physiol Endocrinol Metab 2005;288:E342–E346.
Gomez-Sanchez EP, Fort C, Thwaites D: Central mineralocorticoid receptor antagonism blocks hypertension in Dahl S/JR rats. Am J Physiol 1992;262:E96–E99.
Gomez-Sanchez EP, Samuel J, Vergara G, Ahmad N: Effect of 3β-hydroxysteroid dehydrogenase inhibition by trilostane on blood pressure in the Dahl salt-sensitive rat. Am J Physiol Regul Integr Comp Physiol 2005;288:R389–R393.
Tremblay A, Parker KL, Lehoux JG: Dietary potassium supplementation and sodium restriction stimulate aldosterone synthase but not 11b-hydroxylase P-450 messenger ribonucleic acid accumulation in rat adrenals and require angiotensin II production. Endocrinology 1992;130:3152–3158.
Romero DG, Plonczynski M, Vergara GR, Gomez-Sanchez EP, Gomez-Sanchez CE: Angiotensin II early regulated genes in H295R human adrenocortical cells. Physiol Genomics 2004;19:106–116.
Jo H, Yang EK, Lee WJ, Park KY, Kim HJ, Park JS: Gene expression of central and peripheral renin-angiotensin system components upon dietary sodium intake in rats. Regul Pept 1996;67:115–121.
Ye P, Kenyon CJ, MacKenzie SM, Seckl JR, Fraser R, Connell JM, Davies E: Regulation of aldosterone synthase gene expression in the rat adrenal gland and central nervous system by sodium and angiotensin II. Endocrinology 2003;144:3321–3328.
Felder RB, Francis J, Weiss RM, Zhang ZH, Wei SG, Johnson AK: Neurohumoral regulation in ischemia-induced heart failure: role of the forebrain. Ann NY Acad Sci 2001;940:444–453.
Funder JW: The role of aldosterone and mineralocorticoid receptors in cardiovascular disease. Am J Cardiovasc Drugs 2007;7:151–157.
Gomez-Sanchez EP, Venkataraman MT, Thwaites D: ICV infusion of corticosterone antagonizes ICV-aldosterone hypertension. Am J Physiol 1990;258:E649–E653.
Pearce D, Naray-Fejes-Toth A, Fejes-Toth G: Determinants of subnuclear organization of mineralocorticoid receptor characterized through analysis of wild type and mutant receptors. J Biol Chem 2002;277:1451–1456.
Lombes M, Farman N, Oblin ME: Immunohistochemical localization of renal mineralocorticoid receptor by using an anti-idiotypic antibody that is an internal image of aldosterone. Proc Natl Acad Sci 1990;87:1086–1088.
Couette B, Fagart J, Jalaguier S, Lombes M, Souque A, Rafestin-Oblin ME: Ligand-induced conformational change in the human mineralocorticoid receptor occurs within its hetero-oligomeric structure. Biochem J 1996;315:421–427.
Fejes-Toth G, Pearce D, Naray-Fejes-Toth A: Subcellular localization of mineralocorticoid receptors in living cells: effects of receptor agonists and antagonists. Proc Natl Acad Sci USA 1998;95:2973–2978.
Nishi M, Tanaka M, Matsuda K, Sunaguchi M, Kawata M: Visualization of glucocorticoid receptor and mineralocorticoid receptor interactions in living cells with GFP-based fluorescence resonance energy transfer. J Neurosci 2004;24:4918–4927.
Trapp T, Holsboer F: Ligand-induced conformational changes in the mineralocorticoid receptor analyzed by protease mapping. Biochem Biophys Res Commun 1995;215:286–291.
Trapp T, Rupprecht R, Castren M, Reul JM, Holsboer F: Heterodimerization between mineralocorticoid and glucocorticoid receptor: a new principle of glucocorticoid action in the CNS. Neuron 1994;13:1457–1462.
Rupprecht R, Arriza J, Spengler D, Reul JMHM, Evans RM, Holsboer F, Damm K: Transactivation and synergistic properties of the mineralocorticoid receptor: relationship to the glucocorticoid receptor. Mol Endocrinol 1993;7:597–603.
Meijer OC, Steenbergen PJ, De Kloet ER: Differential expression and regional distribution of steroid receptor coactivators SRC-1 and SRC-2 in brain and pituitary. Endocrinology 2000;141:2192–2199.
Pitt B, Zannad F, Cody R, Castaigne APA, Palensky J, Wittes J: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study investigators. N Engl J Med 1999;341:709–717.
Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M: Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309–1321.
Hollenberg NK: Aldosterone in the development and progression of renal injury. Kidney Int 2004;66:1–9.
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