| Transgenic expression of a dominant negative K(ATP) channel subunit in the mouse endothelium: effects on coronary flow and endothelin-1 secretion. | |
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MedLine Citation:
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PMID: 17341678 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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K(ATP) channels are involved in regulating coronary function, but the contribution of endothelial K(ATP) channels remains largely uncharacterized. We generated a transgenic mouse model to specifically target endothelial K(ATP) channels by expressing a dominant negative Kir6.1 subunit only in the endothelium. These animals had no obvious overt phenotype and no early mortality. Histologically, the coronary endothelium in these animals was preserved. There was no evidence of increased susceptibility to ergonovine-induced coronary vasospasm. However, isolated hearts from these animals had a substantially elevated basal coronary perfusion pressure. The K(ATP) channel openers, adenosine and levcromakalim, decreased the perfusion pressure whereas the K(ATP) channel blocker glibenclamide failed to produce a vasoconstrictive response. The inducible endothelial nitric oxide pathway was intact, as evidenced by vasodilation caused by bradykinin. In contrast, basal endothelin-1 release was significantly elevated in the coronary effluent from these hearts. Treatment of mice with bosentan (endothelin-1 receptor antagonist) normalized the coronary perfusion pressure, demonstrating that the elevated endothelin-1 release was sufficient to account for the increased coronary perfusion pressure. Pharmacological blockade of K(ATP) channels led to elevated endothelin-1 levels in the coronary effluent of isolated mouse and rat hearts as well as enhanced endothelin-1 secretion from isolated human coronary endothelial cells. These data are consistent with a role for endothelial K(ATP) channels to control the coronary blood flow by modulating the release of the vasoconstrictor, endothelin-1. |
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Authors:
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Brian Malester; Xiaoyong Tong; Ioana Ghiu; Andrianos Kontogeorgis; David E Gutstein; Jie Xu; Karen D Hendricks-Munoz; William A Coetzee |
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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 Date: 2007-03-06 |
Journal Detail:
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Title: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology Volume: 21 ISSN: 1530-6860 ISO Abbreviation: FASEB J. Publication Date: 2007 Jul |
Date Detail:
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Created Date: 2007-06-26 Completed Date: 2007-08-15 Revised Date: 2007-12-03 |
Medline Journal Info:
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Nlm Unique ID: 8804484 Medline TA: FASEB J Country: United States |
Other Details:
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Languages: eng Pagination: 2162-72 Citation Subset: IM |
Affiliation:
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Department of Pediatrics, NYU School of Medicine, 560 First Ave., New York, NY 10016, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphate
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physiology Animals Bradykinin / pharmacology Coronary Circulation / physiology* Diazoxide / pharmacology Electrocardiography / drug effects Endothelin-1 / secretion* Endothelium, Vascular / metabolism*, physiopathology, secretion Ergonovine / pharmacology Exocytosis / physiology Gene Expression Regulation Genes, Synthetic Glyburide / pharmacology Mice Mice, Transgenic Point Mutation Potassium Channel Blockers / pharmacology Potassium Channels, Inwardly Rectifying / chemistry, genetics, physiology* Pressure Rats Rats, Sprague-Dawley Tolbutamide / pharmacology Vasoconstriction / drug effects Vasoconstrictor Agents / pharmacology Vasodilation / drug effects Vasodilator Agents / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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HL 081336/HL/NHLBI NIH HHS; HL64838/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Endothelin-1; 0/Potassium Channel Blockers; 0/Potassium Channels, Inwardly Rectifying; 0/Vasoconstrictor Agents; 0/Vasodilator Agents; 0/uK-ATP-1 potassium channel; 10238-21-8/Glyburide; 364-98-7/Diazoxide; 56-65-5/Adenosine Triphosphate; 58-82-2/Bradykinin; 60-79-7/Ergonovine; 64-77-7/Tolbutamide |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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