| Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. | |
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MedLine Citation:
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PMID: 18391097 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Angiotensin-converting enzyme 2 (ACE2) is a key renin-angiotensin system enzyme involved in balancing the adverse effects of angiotensin II on the cardiovascular system, and its overexpression by gene transfer is beneficial in cardiovascular disease. Therefore, our objectives were 2-fold: to identify compounds that enhance ACE2 activity using a novel conformation-based rational drug discovery strategy and to evaluate whether such compounds reverse hypertension-induced pathophysiologies. We used a unique virtual screening approach. In vitro assays revealed 2 compounds (a xanthenone and resorcinolnaphthalein) that enhanced ACE2 activity in a dose-dependent manner. Acute in vivo administration of the xanthenone resulted in a dose-dependent transient and robust decrease in blood pressure (at 10 mg/kg, spontaneously hypertensive rats decreased 71+/-9 mm Hg and Wistar-Kyoto rats decreased 21+/-8 mm Hg; P<0.05). Chronic infusion of the xanthenone (120 microg/day) resulted in a modest decrease in the spontaneously hypertensive rat blood pressure (17 mm Hg; 2-way ANOVA; P<0.05), whereas it had no effect in Wistar-Kyoto rats. Strikingly, the decrease in blood pressure was also associated with improvements in cardiac function and reversal of myocardial, perivascular, and renal fibrosis in the spontaneously hypertensive rats. We conclude that structure-based screening can help identify compounds that activate ACE2, decrease blood pressure, and reverse tissue remodeling. Administration of ACE2 activators may be a valid strategy for antihypertensive therapy. |
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Authors:
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José A Hernández Prada; Anderson J Ferreira; Michael J Katovich; Vinayak Shenoy; Yanfei Qi; Robson A S Santos; Ronald K Castellano; Andrew J Lampkins; Vladimir Gubala; David A Ostrov; Mohan K Raizada |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2008-04-07 |
Journal Detail:
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Title: Hypertension Volume: 51 ISSN: 1524-4563 ISO Abbreviation: Hypertension Publication Date: 2008 May |
Date Detail:
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Created Date: 2008-04-18 Completed Date: 2008-05-07 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7906255 Medline TA: Hypertension Country: United States |
Other Details:
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Languages: eng Pagination: 1312-7 Citation Subset: IM |
Affiliation:
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McKnight Brain Institute and Department of Physiology, College of Medicine, University of Florida, Gainesville, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antihypertensive Agents / chemistry, pharmacology*, therapeutic use* Blood Pressure / drug effects, physiology Disease Models, Animal Dose-Response Relationship, Drug Drug Design Enzyme Activators / chemistry, pharmacology*, therapeutic use* Heart / drug effects, physiology Hypertension / drug therapy*, physiopathology Male Peptidyl-Dipeptidase A / drug effects*, metabolism Rats Rats, Inbred SHR Rats, Inbred WKY Resorcinols / pharmacology, therapeutic use Structure-Activity Relationship Xanthenes / pharmacology, therapeutic use |
| Grant Support | |
ID/Acronym/Agency:
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HL56921/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antihypertensive Agents; 0/Enzyme Activators; 0/Resorcinols; 0/Xanthenes; EC 3.4.15.1/Peptidyl-Dipeptidase A; EC 3.4.17.-/angiotensin converting enzyme 2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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