| Natriuretic and antialdosterone actions of chronic oral NEP inhibition during progressive congestive heart failure. | |
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MedLine Citation:
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PMID: 15840018 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Neutral endopeptidase (NEP) degrades atrial natriuretic peptide (ANP) that via cyclic guanosine monophosphate (cGMP) is natriuretic and aldosterone-inhibiting. We hypothesized that chronic oral NEP inhibition (NEPI), initiated in early experimental congestive heart failure (CHF), would delay onset of decreases in sodium excretion during the progression of CHF and, in the severe phase, suppress aldosterone activation and reduce the magnitude of sodium retention. We also hypothesized that chronic NEPI during progressive CHF (PCHF) would improve the natriuretic response to acute volume expansion. METHODS: In a novel canine model that progresses over 38 days from early to moderate and finally severe CHF, we defined the actions of chronic NEPI (candoxatril, 10 mg/kg, orally, twice a day) upon cardiorenal and neurohumoral function as well as the clinical well being of treated and untreated dogs in CHF. RESULTS: From baseline through the moderate phase of CHF, NEPI maintained sodium excretion. In contrast, in moderate CHF, sodium excretion was reduced compared to the early phase in the controls. In severe CHF, sodium excretion was higher with NEPI compared to control. Chronic NEPI also resulted in lower plasma aldosterone as compared to controls. In severe CHF, the natriuretic response to acute saline volume expansion was enhanced with oral NEPI as compared to control. CONCLUSION: This study supports the conclusion that chronic oral NEPI delays the onset of reduction in sodium excretion during the transition from early to severe CHF in this model of PCHF. This therapeutic strategy also improved the natriuretic response to acute volume expansion in severe CHF while enhancing ANP and suppressing aldosterone activation. Thus, these studies demonstrated a selective renal and adrenal action of chronic NEPI in heart failure indicating a therapeutic potential. |
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Authors:
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Fernando L Martin; Tracy L Stevens; Alessandro Cataliotti; John A Schirger; Daniel D Borgeson; Margaret M Redfield; Andreas Luchner; John C Burnett |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Kidney international Volume: 67 ISSN: 0085-2538 ISO Abbreviation: Kidney Int. Publication Date: 2005 May |
Date Detail:
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Created Date: 2005-04-20 Completed Date: 2005-08-22 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0323470 Medline TA: Kidney Int Country: United States |
Other Details:
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Languages: eng Pagination: 1723-30 Citation Subset: IM |
Affiliation:
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Cardiorenal Research Laboratory, the Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA. martin.fernando@mayo.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Administration, Oral Aldosterone / blood Aldosterone Antagonists / administration & dosage, pharmacology* Animals Atrial Natriuretic Factor / metabolism Cyclic GMP / metabolism Disease Models, Animal Dogs Heart / drug effects, physiopathology Heart Failure / drug therapy*, physiopathology Indans / administration & dosage, pharmacology Kidney / drug effects, physiopathology Male Natriuresis / drug effects* Neprilysin / antagonists & inhibitors* Propionates / administration & dosage, pharmacology Protease Inhibitors / administration & dosage, pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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HL-36634/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Aldosterone Antagonists; 0/Indans; 0/Propionates; 0/Protease Inhibitors; 118785-03-8/candoxatril; 52-39-1/Aldosterone; 7665-99-8/Cyclic GMP; 85637-73-6/Atrial Natriuretic Factor; EC 3.4.24.11/Neprilysin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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