| Phosphoramidon blocks the pressor activity of big endothelin[1-39] and lowers blood pressure in spontaneously hypertensive rats. | |
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MedLine Citation:
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PMID: 1725358 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In porcine aortic endothelial cells, the 21-amino acid peptide endothelin-1 (ET-1) is formed from a 39-amino acid intermediate big endothelin (big ET) by a putative endothelin-converting enzyme (ECE) that cleaves the 39-mer at the Trp21-Val22 bond. Because big ET has less than 1% of the contractile activity of ET-1, inhibition of ECE should effectively block the biological effects of big ET. Big ET injected intravenously into anesthetized rats produces a sustained pressor response that presumably is due to conversion of big ET to ET-1 by ECE. We determined the type of protease activity responsible for this conversion by evaluating the effectiveness of protease inhibitors in blocking the pressor response to big ET in ganglion-blocked anesthetized rats. The serine protease inhibitor leupeptin, the cysteinyl protease inhibitor E-64, and the metalloprotease inhibitors captopril and kelatorphan were ineffective at blocking the pressor response to big ET. However, the metalloprotease inhibitors phosphoramidon and thiorphan both dose-dependently inhibited the pressor response to big ET, although phosphoramidon was substantially more potent than thiorphan. None of the inhibitors blocked the pressor response to ET-1 and none had any effect on blood pressure when administered alone as an i.v. bolus to the ganglion-blocked anesthetized rat. However, phosphoramidon infused intravenously at 20 mg/kg/h for 4 h lowered the mean arterial pressure (MAP) in conscious spontaneously hypertensive rats (SHRs) whereas kelatorphan at the same dose did not. Our results suggest that ECE is a novel metalloprotease and that ECE inhibitors could have therapeutic potential for the treatment of hypertension. |
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Authors:
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E G McMahon; M A Palomo; W M Moore |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Journal of cardiovascular pharmacology Volume: 17 Suppl 7 ISSN: 0160-2446 ISO Abbreviation: J. Cardiovasc. Pharmacol. Publication Date: 1991 |
Date Detail:
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Created Date: 1992-05-12 Completed Date: 1992-05-12 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 7902492 Medline TA: J Cardiovasc Pharmacol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: S29-33 Citation Subset: IM |
Affiliation:
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Searle Research & Development, G. D. Searle & Co., St. Louis, MO 63167. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Aspartic Acid Endopeptidases / antagonists & inhibitors Blood Pressure / drug effects* Dose-Response Relationship, Drug Endothelin-1 Endothelins / antagonists & inhibitors* Glycopeptides / pharmacology* Hypertension / drug therapy*, physiopathology Male Metalloendopeptidases Protease Inhibitors / pharmacology Protein Precursors / antagonists & inhibitors* Rats Rats, Inbred SHR Rats, Inbred Strains Rats, Inbred WKY |
| Chemical | |
Reg. No./Substance:
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0/Endothelin-1; 0/Endothelins; 0/Glycopeptides; 0/Protease Inhibitors; 0/Protein Precursors; 36357-77-4/phosphoramidon; EC 3.4.23.-/Aspartic Acid Endopeptidases; EC 3.4.24.-/Metalloendopeptidases; EC 3.4.24.71/endothelin-converting enzyme |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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