Action of New Steroids in Blocking Effects of Aldosterone and Deoxycorticosterone on Salt

Kagawa, C. M.; Cella, James A.; Arman, C. G. Van

doi:10.1126/science.126.3281.1015

Cited by 273 publications

(87 citation statements)

References 3 publications

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“…The urinary Na/K ratio has widely been used to evaluate aldosterone activity at the distal nephron and collecting duct (31,32). Accordingly, the sodium-retaining stage (group A rats with cirrhosis) in both protocols 1 and 2 was associated with markedly decreased urinary Na/K ratio, indicating an increased aldosterone effect in the distal nephron.…”

Section: Decreased Urinary Na/k Ratio In Group a But Not In Group B Omentioning

confidence: 99%

Increased Apical Targeting of Renal Epithelial Sodium Channel Subunits and Decreased Expression of Type 2 11β-Hydroxysteroid Dehydrogenase in Rats with CCl4-Induced Decompensated Liver Cirrhosis

Kim¹,

Schou²,

Peters³

et al. 2005

Journal of the American Society of Nephrology

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It was hypothesized that dysregulation of renal epithelial sodium channel (ENaC) subunits and/or 11␤-hydroxysteroid dehydrogenase (11␤HSD2) may play a role in the increased sodium retention in liver cirrhosis (LC). Experimental LC was induced in rats by CCl 4 (1 ml/kg, intraperitoneally, twice a week) for 12 wk (protocol 1) or for 11 wk (protocol 2). In both protocols, one group of rats with cirrhosis showed significantly decreased urinary sodium excretion and urinary Na/K ratio (group A), whereas a second group exhibited normal urinary sodium excretion (group B) compared with controls, even though extensive ascites was seen in both groups of rats with cirrhosis. In group A, protein abundance of ␣-ENaC was unchanged, whereas ␤-ENaC abundance was decreased in the cortex/outer stripe of outer medulla compared with controls. The ␥-ENaC underwent a complex change associated with increased abundance of the 70-kD band with a concomitant decrease in the main 85-kD band, corresponding to an aldosterone effect. In contrast, no changes in the abundance of ENaC subunit were observed in group B. Immunoperoxidase microscopy revealed an increased apical targeting of ␣-, ␤-, and ␥-ENaC subunits in distal convoluted tubule (DCT2), connecting tubule (CNT), and cortical and medullary collecting duct segments in group A but not in group B. Immunolabeling intensity of 11␤HSD2 in the DCT2, CNT, and cortical collecting duct was significantly reduced in group A but not in group B, and this was confirmed by immunoblotting. In conclusion, increased apical targeting of ENaC subunits combined with diminished abundance of 11␤HSD2 in the DCT2, CNT, and cortical collecting duct is likely to play a role in the sodium retaining stage of liver cirrhosis.

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Section: Decreased Urinary Na/k Ratio In Group a But Not In Group B Omentioning

confidence: 99%

Increased Apical Targeting of Renal Epithelial Sodium Channel Subunits and Decreased Expression of Type 2 11β-Hydroxysteroid Dehydrogenase in Rats with CCl4-Induced Decompensated Liver Cirrhosis

Kim¹,

Schou²,

Peters³

et al. 2005

Journal of the American Society of Nephrology

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“…Also confirmatory of its importance in CHF was the efficacy of spironolactone, an ALDO receptor antagonist introduced into clinical practice 45 years ago, in counteracting Na + retention and alleviating oedema. [4][5][6][7][8] A recent resurgence of interest in this steroid molecule in CHF has been driven by several observations. 9 In brief, this included: a recognition of ALDO's broader range of actions that extended beyond classic target tissues and which were associated with an adverse structural remodelling of the cardiovasculature that contributes to pathophysiologic expressions and progressive nature of CHF;…”

Section: Introductionmentioning

confidence: 99%

Toward a broader understanding of aldosterone in congestive heart failure

Weber

Sun

Wodi

et al. 2003

J Renin Angiotensin Aldosterone Syst

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Discovered some 50 years ago, aldosterone (ALDO) has come to be recognised as a mineralocorticoid hormone with well-known endocrine properties in epithelial cells that contribute to the pathophysiology of congestive heart failure. This includes Na + in such non-epithelial cells as peripheral blood mononuclear cells; its influence on endothelial cell function; and its central actions that involve regulation of cerebrospinal fluid composition produced by epithelial cells of the choroid plexus, activity of the hypothalamic paraventricular nucleus involved in Na + appetite, Na + and H 2 O excretion and sympathetic nerve activity, and the regulation of TNF-α production from central and/or peripheral sources. Extra-adrenal steroidogenesis and auto/paracrine properties of ALDO generated de novo in the cardiovasculature are now under investigation and preliminary findings suggest they contribute to tissue repair. The past decade has witnessed a revival of interest in this steroid molecule. In years to come, an even broader understanding of ALDO's contribution to the pathophysiology of congestive heart failure will undoubtedly emerge.

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“…SC8109 (17-hydroxy-3-oxo-19-nor-17a-pregn-4-ene-21 car-boxylic acid, y lactone) structurally resembles spironolactone ( Figure 1) which has found use in the treatment of oedematous states and essential hypertension (Ochs et al, 1978). Both compounds have been shown to be competitive aldosterone antagonists in animals (Kagawa, Cella & Van Arman, 1957;Liddle, 1957;Kagawa, Sturtevant 1959 ;Slater et al, 1959;Kagawa 1960) and in man (Liddle, 1957;1958;Ross & Bethune, 1959;Gantt, 1961). SC8109 was effective in primary hyperaldosteronism (Salassa, Mattox & Power, 1958), essential hypertension (Bolte et al, 1958) and oedema secondary to nephrotic syndrome (Slater etal., 1959), congestive cardiac failure (Liddle, 1957(Liddle, , 1958Bolte et al, 1958;Slater et al, 1959) and hepatic cirrhosis (Liddle 1957(Liddle , 1958Kerr etal., 1958).…”

Section: Introductionmentioning

confidence: 99%

Quantitative comparison of aldosterone antagonists in normal human subjects: prediction of therapeutic potency.

McInnes¹,

Harrison²,

Shelton³

et al. 1981

Brit J Clinical Pharma

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1 The potency of single doses of the aldosterone antagonist SC8109 relative to spironolactone in reversing the urinary electrolyte effects of fludrocortisone was examined in a double-blind, balanced, crossover study in six healthy volunteers. 2 For the urinary ratio log10 10 Na/K, the relative potency of SC8109: spironolactone on a weight basis was 0.08:1 (95% confidence limits 0.04-0.13:1). 3 The potency of SC8109 relative to spironolactone for natriuresis and antikaliuresis was 0.10:1 and 0.05:1, respectively. 4 The results show excellent agreement with clinical experience where SC8109 was considered to have one tenth the potency of spironolactone. We suggest that the human bioassay employed in this study provides quantitative information which should be predictive of the therapeutic potency of aldosterone antagonists.

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Action of New Steroids in Blocking Effects of Aldosterone and Deoxycorticosterone on Salt

Cited by 273 publications

References 3 publications

Increased Apical Targeting of Renal Epithelial Sodium Channel Subunits and Decreased Expression of Type 2 11β-Hydroxysteroid Dehydrogenase in Rats with CCl4-Induced Decompensated Liver Cirrhosis

Increased Apical Targeting of Renal Epithelial Sodium Channel Subunits and Decreased Expression of Type 2 11β-Hydroxysteroid Dehydrogenase in Rats with CCl4-Induced Decompensated Liver Cirrhosis

Toward a broader understanding of aldosterone in congestive heart failure

Quantitative comparison of aldosterone antagonists in normal human subjects: prediction of therapeutic potency.

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