Exclusion of corticosterone from epithelial mineralocorticoid receptors is insufficient for selectivity of aldosterone action: In vivo binding studies
ABSTRACT Adrenalectomized weanling rats injected with [3H]aldosterone plus excess RU486, with or without a range of doses of nonradioactive aldosterone or corticosterone, show tissue-specific patterns of competition for tracer binding to mineralocorticoid receptors (MR). From detailed dose-response curves, corticosterone in vivo shows approximately 3% the apparent affinity of aldosterone for MR in colon and kidney, approximately 30% for those in the heart, and approximately 300% in the hippocampus. We interpret these data as evidence that 1) relatively low levels of aldosterone cross the blood-brain barrier; and 2) specificity-conferring mechanisms in addition to the exclusion of corticosterone from epithelial MR are required for selective aldosterone action in sodium homeostasis.
- SourceAvailable from: John Funder
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- "In epithelia aldosterone-selectivity of mineralocorticoid receptor activation is procured by co-expression of the enzyme 11β-hydroxysteroid dehydrogenase , which is also expressed in certain nonepithelial tissues (vascular wall, placenta, nucleus tractus solitarius), making them similarly physiological aldosterone target tissues. It was initially thought , and is still commonly taught, that 11β-hydroxysteroid dehydrogenase operates by excluding glucocorticoids from protected mineralocorticoid receptors via conversion to receptorinactive 11-keto congeners (e.g. cortisol to cortisone). "
ABSTRACT: The hormone aldosterone has a well-recognized physiological role in epithelial fluid and electrolyte homeostasis, and more recently defined pathophysiological roles in the cardiovascular system. The term "risk factor" implies an active role in pathophysiology, with levels lower (e.g. HDL) or higher (e.g. LDL, BP) than normal contributing to an increased likelihood of morbidity and/or mortality. In this regard, primary aldosteronism represents a classic illustration of aldosterone as a cardiovascular risk factor. In this syndrome of (relatively) autonomous aldosterone secretion, the effects of elevated hormone levels are on a range of organs and tissues-the heart, blood vessels and brain, inter alia. In other cardiovascular disorders (e.g. CCF, EH) while an elevation of aldosterone levels is often regarded as a risk factor, it is more correctly a response to the severity of disease (or to treatment intervention), rather than necessarily a risk factor with a primary role in disease progression. An enduring enigma relevant to any discussion of aldosterone as a risk factor is that very high levels of aldosterone in response to chronic sodium deficiency have homeostatic (and protective of cardiovascular) functions, while the considerably lower levels commonly seen in primary aldosteronism are incontrovertibly damaging. A final section of the paper will thus propose a mechanism which might solve this enigma, based on the commonalities-and a single crucial difference-in the factors stimulating the secretion of aldosterone and endogenous ouabain from the zona glomerulosa of the adrenal gland.Biochimica et Biophysica Acta 12/2010; 1802(12):1188-92. DOI:10.1016/j.bbadis.2010.08.005 · 4.66 Impact Factor
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- "MR in extra-renal rat tissues bind aldosterone and corticosterone with similar affinities (Krozowski and Funder, 1983) while human MR (Kd ~1 nmol·L -1 ) has (10–40 fold) higher affinity for cortisol than GR (Arriza et al., 1987). Thus, the selectivity shown by MR for aldosterone over cortisol (which is present in the plasma in concentrations 100–1000 times higher than aldosterone) in vivo is largely dependent on pre-receptor metabolism of glucocorticoids by 11-HSD type 2 [(Stewart and Krozowski, 1999); see below], although other processes also have a role (Funder and Myles, 1996). Consequently , the cellular response to glucocorticoids will depend upon whether the target tissue expresses GR and/or MR and/or the isozymes of 11-HSD [discussed in (Walker, 2007b)]. "
ABSTRACT: The therapeutic potential for manipulation of glucocorticoid metabolism in cardiovascular disease was revolutionized by the recognition that access of glucocorticoids to their receptors is regulated in a tissue-specific manner by the isozymes of 11beta-hydroxysteroid dehydrogenase. Selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 have been shown recently to ameliorate cardiovascular risk factors and inhibit the development of atherosclerosis. This article addresses the possibility that inhibition of 11beta-hydroxsteroid dehydrogenase type 1 activity in cells of the cardiovascular system contributes to this beneficial action. The link between glucocorticoids and cardiovascular disease is complex as glucocorticoid excess is linked with increased cardiovascular events but glucocorticoid administration can reduce atherogenesis and restenosis in animal models. There is considerable evidence that glucocorticoids can interact directly with cells of the cardiovascular system to alter their function and structure and the inflammatory response to injury. These actions may be regulated by glucocorticoid and/or mineralocorticoid receptors but are also dependent on the 11beta-hydroxysteroid dehydrogenases which may be expressed in cardiac, vascular (endothelial, smooth muscle) and inflammatory (macrophages, neutrophils) cells. The activity of 11beta-hydroxysteroid dehydrogenases in these cells is dependent upon differentiation state, the action of pro-inflammaotory cytokines and the influence of endogenous inhibitors (oxysterols, bile acids). Further investigations are required to clarify the link between glucocorticoid excess and cardiovascular events and to determine the mechanism through which glucocorticoid treatment inhibits atherosclerosis/restenosis. This will provide greater insights into the potential benefit of selective 11beta-hydroxysteroid dehydrogenase inhibitors in treatment of cardiovascular disease.British Journal of Pharmacology 03/2009; 156(5):689-712. DOI:10.1111/j.1476-5381.2008.00047.x · 4.99 Impact Factor
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- "The distribution of these neurons overlaps a region of the NTS, just ventral to the area postrema, that lacks a complete blood-brain barrier (BBB, Gross et al., 1990). This location may allow the HSD2 neurons increased exposure to blood-borne aldosterone, which only weakly penetrates the BBB, particularly in comparison to the glucocorticoid corticosterone (Pardridge and Mietus, 1979; Funder and Myles, 1996), with which it must compete for mineralocorticoid receptors (MRs) in cells without HSD2. "
ABSTRACT: The HSD2 (11-beta-hydroxysteroid dehydrogenase type 2-expressing) neurons in the nucleus of the solitary tract (NTS) of the rat are aldosterone-sensitive and have been implicated in sodium appetite. The central nucleus of the amygdala (CeA) has been shown to modulate salt intake in response to aldosterone, so we investigated the connections between these two sites. A prior retrograde tracing study revealed only a minor projection from the HSD2 neurons directly to the CeA, but these experiments suggested that a more substantial projection may be relayed through the parabrachial nucleus. Small injections of cholera toxin beta subunit (CTb) into the external lateral parabrachial subnucleus (PBel) produced both retrograde cell body labeling in the HSD2 neurons and anterograde axonal labeling in the lateral subdivision of the CeA. Also, injections of either CTb or Phaseolus vulgaris leucoagglutinin into the medial subdivision of the CeA labeled a descending projection from the amygdala to the medial NTS. Axons from the medial CeA formed numerous varicosities and terminals enveloping the HSD2 neurons. Complementary CTb injections, centered in the HSD2 subregion of the NTS, retrogradely labeled neurons in the medial CeA. These bidirectional projections could form a functional circuit between the HSD2 neurons and the CeA. The HSD2 neurons may represent one of the functional inputs to the lateral CeA, and their activity may be modulated by a return projection from the medial CeA. This circuit could provide a neuroanatomical basis for the modulation of salt intake by the CeA.The Journal of Comparative Neurology 08/2006; 497(4):646-57. DOI:10.1002/cne.21019 · 3.51 Impact Factor