4-Aminopyridine restores impaired hypoxic pulmonary vasoconstriction in endotoxemic mice.
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.
Spöhr
Fabian
F
Department of Anaesthesiology, Ruprecht-Karls-University, Heidelberg, Germany.
Busch
Cornelius J
CJ
Reich
Christian
C
Motsch
Johann
J
Gebhard
Martha M
MM
Kuebler
Wolfgang M
WM
Bloch
Kenneth D
KD
Weimann
Jörg
J
D015761:4-Aminopyridine / Q000627:therapeutic use*; D000465:Algorithms; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000188:drug therapy* / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010477:Perfusion; D026902:Potassium Channel Blockers / Q000627:therapeutic use*; D015221:Potassium Channels / Q000096:biosynthesis; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D014661:Vasoconstriction / Q000187:drug effects*
D008070:Lipopolysaccharides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012333:RNA, Messenger; D000804:Angiotensin II; D015761:4-Aminopyridine