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      Alpha-2A Adrenoceptor Agonist Guanfacine Restores Diuretic Efficiency in Experimental Cirrhotic Ascites: Comparison with Clonidine

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          Abstract

          Background

          In human cirrhosis, adrenergic hyperfunction causes proximal tubular fluid retention and contributes to diuretic-resistant ascites, and clonidine, a sympatholytic drug, improves natriuresis in difficult-to-treat ascites.

          Aim

          To compare clonidine (aspecific α 2-adrenoceptor agonist) to SSP-002021R (prodrug of guanfacine, specific α 2A-receptor agonist), both associated with diuretics, in experimental cirrhotic ascites.

          Methods and Results

          Six groups of 12 rats were studied: controls (G1); controls receiving furosemide and potassium canrenoate (G2); rats with ascitic cirrhosis due to 14-week CCl 4 treatment (G3); cirrhotic rats treated (over the 11 th-14 th CCl 4 weeks) with furosemide and canrenoate (G4), furosemide, canrenoate and clonidine (G5), or diuretics and SSP002021R (G6). Three rats of each group had their hormonal status and renal function assessed at the end of 11 th, 12 th, 13 th, and 14 th weeks of respective treatments.Cirrhotic rats in G3 and G4 gained weight over the 12 th-14 th CCl 4 weeks. In G4, brief increase in sodium excretion over the 11 th-12 th weeks preceded worsening of inulin clearance and natriuresis (diuretic resistance). In comparison with G4, the addition of clonidine (G5) or guanfacine (G6) to diuretics improved, respectively, sodium excretion over the 11 th-12 th CCl 4 weeks, or GFR and electrolytes excretion over the 13 th-14 th CCl 4 weeks. Natriuretic responses in G5 and G6 were accompanied by reduced catecholamine serum levels.

          Conclusions

          α 2A-receptor agonists restore glomerular filtration rate and natriuresis, and delay diuretic-resistant ascites in experimental advanced cirrhosis. Clonidine ameliorates diuretic-dependent natriuresis just for a short time.

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          Most cited references32

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          Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club.

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            Cardiovascular regulation in mice lacking alpha2-adrenergic receptor subtypes b and c.

            alpha2-Adrenergic receptors (alpha2ARs) are essential components of the neural circuitry regulating cardiovascular function. The role of specific alpha2AR subtypes (alpha2a, alpha2b, and alpha2c) was characterized with hemodynamic measurements obtained from strains of genetically engineered mice deficient in either alpha2b or alpha2c receptors. Stimulation of alpha2b receptors in vascular smooth muscle produced hypertension and counteracted the clinically beneficial hypotensive effect of stimulating alpha2a receptors in the central nervous system. There were no hemodynamic effects produced by disruption of the alpha2c subtype. These results provide evidence for the clinical efficacy of more subtype-selective alpha2AR drugs.
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              • Article: not found

              Hyponatremia in cirrhosis: from pathogenesis to treatment.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                6 July 2016
                2016
                : 11
                : 7
                : e0158486
                Affiliations
                [1 ]Division of Gastroenterology, Gradenigo Hospital, Torino, Italy
                [2 ]Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
                [3 ]Clinical Biochemistry Laboratory, San Giovanni Battista Hospital, Torino, Italy
                Taipei Veterans General Hospital, TAIWAN
                Author notes

                Competing Interests: This study was funded by the pharmaceutical company Shire. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: GS MA MP. Performed the experiments: RM GM. Analyzed the data: GS MA RM GM MP. Contributed reagents/materials/analysis tools: RM GM. Wrote the paper: GS MA RM GM MP.

                Article
                PONE-D-16-10475
                10.1371/journal.pone.0158486
                4934922
                27384184
                9495881c-42e6-4b07-8854-a9e97e3ecfa8
                © 2016 Sansoè et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 21 March 2016
                : 16 June 2016
                Page count
                Figures: 4, Tables: 3, Pages: 13
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100007343, Shire;
                Award ID: 1/2011-2012
                Award Recipient : Giovanni Sansoe'
                This study was funded by the pharmaceutical company Shire. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Diuretics
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Ascites
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Cirrhosis
                Biology and Life Sciences
                Anatomy
                Renal System
                Medicine and Health Sciences
                Anatomy
                Renal System
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Excretion
                Medicine and Health Sciences
                Physiology
                Physiological Processes
                Excretion
                Biology and Life Sciences
                Physiology
                Renal Physiology
                Glomerular Filtration Rate
                Medicine and Health Sciences
                Physiology
                Renal Physiology
                Glomerular Filtration Rate
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Plasma
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Hematology
                Blood
                Blood Plasma
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Urine
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Urine
                Biology and Life Sciences
                Physiology
                Body Fluids
                Urine
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Urine
                Custom metadata
                All relevant data are within the paper.

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