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.
[Show abstract][Hide abstract] ABSTRACT: The stretch of cardiac muscle increases developed force in two phases. The first phase, which occurs rapidly, constitutes the well-known Frank-Starling mechanism and it is generally attributed to enhanced myofilament responsiveness to Ca2+. The second phase or slow force response (SFR) occurs gradually and is due to an increase in the calcium transient amplitude as a result of a stretch-triggered autocrine/paracrine mechanism. We previously showed that Ca2+ entry through reverse Na+/Ca2+ exchange underlies the SFR, as the final step of an autocrine/paracrine cascade involving release of angiotensin II/endothelin, and a Na+/H+ exchanger (NHE-1) activation-mediated rise in Na+. In the present review we mainly focus on our three latest contributions to the understanding of this signalling pathway triggered by myocardial stretch: 1) The finding that an increased production of reactive oxygen species (ROS) from mitochondrial origin is critical in the activation of the NHE-1 and therefore in the genesis of the SFR; 2) the demonstration of a key role played by the transactivation of the epidermal growth factor receptor; and 3) the involvement of mineralocorticoid receptors (MR) activation in the stretch-triggered cascade leading to the SFR. Among these novel contributions, the critical role played by the MR is perhaps the most important one. This finding may conceivably provide a mechanistic explanation to the recently discovered strikingly beneficial effects of MR antagonism in humans with cardiac hypertrophy and failure.
Current Cardiology Reviews 08/2013; 9(3). DOI:10.2174/1573403X113099990034
"In the kidneys it increases tubular sodium reabsorption, leading to an increase in renal sodium retention and a decrease in urinary sodium excretion. Aldosterone is a steroid that can easily enter the brain (Hendler and Livingston, 1978; De Nicola et al., 1981; Birmingham et al., 1984; Funder and Myles, 1996; Uhr et al., 2002). Acting via mineralocorticoid receptors, aldosterone increases sympathetic nerve activity by up regulating the brain RAS components and induction of oxidative stress in the hypothalamus (Zhang et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Chronic elevation of the sympathetic nervous system has been identified as a major contributor to the complex pathophysiology of hypertension, states of volume overload - such as heart failure - and progressive kidney disease. It is also a strong determinant for clinical outcome. This review focuses on the central role of the kidneys in the pathogenesis of sympathetic hyperactivity. As a consequence, renal denervation may be an attractive option to treat sympathetic hyperactivity. The review will also focus on first results and the still remaining questions of this new treatment option.
Frontiers in Physiology 02/2012; 3:29. DOI:10.3389/fphys.2012.00029 · 3.53 Impact Factor
"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). "
[Show abstract][Hide abstract] 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.
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