| 4-Aminopyridine restores impaired hypoxic pulmonary vasoconstriction in endotoxemic mice. | |
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MedLine Citation:
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PMID: 17893456 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Hypoxic pulmonary vasoconstriction (HPV) is impaired during inflammatory lung processes such as pneumonia or the acute respiratory distress syndrome. Voltage-gated potassium channels play a central role in mediating HPV. The aim of this study was to determine whether 4-aminopyridine (4-AP), a known voltage-gated potassium channel inhibitor, may restore HPV in sepsis. METHODS: The effects of 0.01, 0.1, and 1.0 mm 4-AP on HPV responsiveness were assessed in isolated lungs of untreated mice and of mice 18 h after lipopolysaccharide injection (20 mg/kg intraperitoneal Escherichia coli 0111:B4 lipopolysaccharide). HPV was quantified as the increase in perfusion pressure in response to hypoxic ventilation in percent of baseline perfusion pressure. Intrinsic pulmonary vascular resistance (R0) and pulmonary vascular distensibility (alpha) were determined by nonlinear regression analysis of pulmonary vascular pressure-flow curves generated during normoxic and hypoxic ventilation, respectively. RESULTS: HPV was impaired in lungs isolated from lipopolysaccharide-challenged mice. Addition of 4-AP to the perfusate did not alter HPV responsiveness in untreated mice but dose dependently restored HPV in endotoxemic mice. Analysis of pulmonary vascular pressure-flow curves revealed that 4-AP (1) counteracted the observed lipopolysaccharide-induced changes in alpha and R0 under normoxic conditions and (2) augmented the hypoxia-induced increase in R0 in lungs of endotoxemic mice. CONCLUSIONS: This study demonstrates that lipopolysaccharide-induced pulmonary vascular hyporesponsiveness to hypoxia can be restored by 4-AP in murine endotoxemia and, thus, may be a new therapeutic approach to treat patients with hypoxemia due to impaired HPV. |
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Authors:
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Fabian Spöhr; Cornelius J Busch; Christian Reich; Johann Motsch; Martha M Gebhard; Wolfgang M Kuebler; Kenneth D Bloch; Jörg Weimann |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Anesthesiology Volume: 107 ISSN: 0003-3022 ISO Abbreviation: Anesthesiology Publication Date: 2007 Oct |
Date Detail:
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Created Date: 2007-09-25 Completed Date: 2007-10-29 Revised Date: 2007-12-03 |
Medline Journal Info:
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Nlm Unique ID: 1300217 Medline TA: Anesthesiology Country: United States |
Other Details:
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Languages: eng Pagination: 597-604 Citation Subset: AIM; IM |
Affiliation:
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Department of Anaesthesiology, Ruprecht-Karls-University, Heidelberg, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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4-Aminopyridine
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therapeutic use* Algorithms Angiotensin II / pharmacology Animals Anoxia / physiopathology* Body Weight / drug effects Dose-Response Relationship, Drug Endotoxemia / drug therapy*, physiopathology* Lipopolysaccharides / antagonists & inhibitors, pharmacology Male Mice Organ Size / drug effects Perfusion Potassium Channel Blockers / therapeutic use* Potassium Channels / biosynthesis Pulmonary Artery / drug effects, physiopathology Pulmonary Circulation / drug effects* RNA, Messenger / biosynthesis Vasoconstriction / drug effects* |
| Grant Support | |
ID/Acronym/Agency:
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HL 74352/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Lipopolysaccharides; 0/Potassium Channel Blockers; 0/Potassium Channels; 0/RNA, Messenger; 11128-99-7/Angiotensin II; 504-24-5/4-Aminopyridine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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