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      Analbuminemic Nagase Rats: Blood Pressure Response to Dietary Salt Challenge

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          Abstract

          Background: The role of albumin on blood pressure response to different salt challenges is not known. Therefore, we studied the blood pressure response of analbuminemic Nagase rats (NAR) to different salt challenges. 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2), the enzyme regulating the glucocorticoid access to the mineralocorticoid receptor, an enzyme that is decreased in humans with salt sensitive hypertension and other diseases with abnormal renal salt retention, was assessed during salt challenges. Methods: Blood pressure was measured continuously by an intra-arterial catheter and a telemetry system in NAR (n = 8). NAR were set successively for 7 days on a normal (0.45% NaCl), high (8% NaCl), low (0.1% NaCl) and normal salt diet again, to assess salt related response in mean systolic (SBP) and diastolic blood pressure (DBP). 11β-HSD2activity was assessed by measuring the urinary (THB + 5α-THB)/THA ratio with gas chromatography – mass spectrometry. Results: Mean SBP and DBP increased with high salt intake (normal salt vs. high salt: SBP: 114 ± 1 vs.119 ± 3 mm Hg, p < 0.01; DBP: 84 ± 1 vs. 88 ± 3 mm Hg; n = 8; p < 0.01). Urinary (THB +5α-THB)/THA ratio increased during the high-salt period when compared to the normal-salt period (high salt vs. normal salt: 0.52 ± 0.10 vs. 0.37 ± 0.07; p = 0.05) indicating decreased 11β-HSD2activity. Conclusion: Analbuminemic Nagase rats express increased blood pressure and reduced 11β-HSD2 activity in response to a high-salt diet.

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          Profiling steroid hormones and urinary steroids

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            Albumin-deficient rat mutant.

            An analbuminemic colony was established from Sprague-Dawley rats. Analbuminemia was inherited as an autosomal recessive trait. The rates of growth and reproduction of the mutant rats were no different from those of normal rats. Biochemically, the mutant was characterized by an extraordinarily low serum albumin content and a hyperlipidemia. Total serum protein in the mutant rat was similar to that of control Sprague-Dawley rats, with increased globulin. Serum cholesterol was inversely correlated with a decrease in albumin; the correlation coefficient for ablumin was --.92. These mutant rats may serve as a model of human familial analbuminemia and may also be useful in elucidating the functional roles of albumin.
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              The role of the 11beta-hydroxysteroid dehydrogenase type 2 in human hypertension.

              The 11 beta-hydroxysteroid dehydrogenase type 2 (11 PHSD2) enzyme inactivates 11 betahydroxy steroids in sodium-transporting epithelia such as the kidney, thus protecting the non-selective mineralocorticoid receptor (MR) from occupation by cortisol in humans. Inhibition by xenobiotics such as liquorice or mutations in the HSD11 B2 gene, as occur in the rare monogenic hypertensive syndrome of apparent mineralocorticoid excess (AME), result in a compromised 11 betaHSD2 enzyme activity, which in turn leads to overstimulation of the MR by cortisol, sodium retention, hypokalaemia, low plasma renin and aldosterone concentrations, and hypertension. Whereas the first patients described with AME had a severe form of hypertension and metabolic derangements, with an increased urinary ratio of cortisol (THF+5alphaTHF) to cortisone (THE) metabolites, more subtle effects of mild 11 beta HSD2 deficiency on blood pressure have recently been observed. Hypertension with no other characteristic signs of AME was found in the heterozygous father of a child with AME, and we described a girl with a homozygous gene mutation resulting in only a slightly reduced 11 beta HSD2 activity causing 'essential' hypertension. Thus, depending on the degree of loss of enzyme activity, 11 beta HSD2 mutations can cause a spectrum of phenotypes ranging from severe, life-threatening hypertension in infancy to a milder form of the disease in adults. Patients with essential hypertension usually do not have overt signs of mineralocorticoid excess, but nevertheless show a positive correlation between blood pressure and serum sodium levels, or a negative correlation with potassium concentrations, suggesting a mineralocorticoid influence. Recent studies revealed a prolonged half-life of cortisol and an increased ratio of urinary cortisol to cortisone metabolites in some patients with essential hypertension. These abnormalities may be genetically determined. A genetic association of a HSD11 B2 flanking microsatellite and hypertension in black patients with end-stage renal disease has been reported. A recent analysis of a CA-repeat allele polymorphism in unselected patients with essential hypertension did not find a correlation between this marker and blood pressure. Since steroid hormones with mineralocorticoid action modulate renal sodium retention, one might hypothesize that genetic impairment of 11 beta HSD2 activity would be more prevalent in salt-sensitive as compared with salt-resistant subjects. Accordingly, we found a significant association between the polymorphic CA-microsatellite marker and salt-sensitivity. Moreover, the mean ratio of urinary cortisol to cortisone metabolites, as a measure for 11betaHSD2 activity, was markedly elevated in salt-sensitive subjects. These findings suggest that variants of the HSD11 B2 gene may contribute to the enhanced blood pressure response to salt in some humans.
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                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                1660-2137
                2006
                September 2006
                28 September 2006
                : 104
                : 2
                : p81-p86
                Affiliations
                Clinic and Policlinic of Nephrology and Hypertension, University Hospital Inselspital, Berne, Switzerland
                Article
                94002 Nephron Physiol 2006;104:p81–p86
                10.1159/000094002
                16785748
                9092109a-a640-4db2-afb4-1212028c9dfb
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 10 March 2005
                : 27 February 2006
                Page count
                Figures: 6, References: 12, Pages: 1
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Mass spectrometry,Salt challenge,11β-Hydroxysteroid dehydrogenase type 2,Nagase analbuminemic rat,Gas chromatography,Hypertension

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