Document Detail

4-Aminopyridine restores impaired hypoxic pulmonary vasoconstriction in endotoxemic mice.
MedLine Citation:
PMID:  17893456     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anesthesiology     Volume:  107     ISSN:  0003-3022     ISO Abbreviation:  Anesthesiology     Publication Date:  2007 Oct 
Date Detail:
Created Date:  2007-09-25     Completed Date:  2007-10-29     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  1300217     Medline TA:  Anesthesiology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  597-604     Citation Subset:  AIM; IM    
Department of Anaesthesiology, Ruprecht-Karls-University, Heidelberg, Germany.
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MeSH Terms
4-Aminopyridine / therapeutic use*
Angiotensin II / pharmacology
Anoxia / physiopathology*
Body Weight / drug effects
Dose-Response Relationship, Drug
Endotoxemia / drug therapy*,  physiopathology*
Lipopolysaccharides / antagonists & inhibitors,  pharmacology
Organ Size / drug effects
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
Reg. No./Substance:
0/Lipopolysaccharides; 0/Potassium Channel Blockers; 0/Potassium Channels; 0/RNA, Messenger; 11128-99-7/Angiotensin II; 504-24-5/4-Aminopyridine

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