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 (R 0 ) and pulmonary vascular distensibility (a) 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 a and R 0 under normoxic conditions and (2) augmented the hypoxia-induced increase in R 0 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.