Abstract
BackgroundATP-regulated potassium channels (KATP) regulate pulmonary vascular tone and are involved in hypoxic pulmonary vasoconstriction (HPV). In patients with inflammation like sepsis or ARDS, HPV is impaired, resulting in a ventilation-perfusion mismatch and hypoxia. Since increase of vascular KATP channel Kir6.1 has been reported in animal models of endotoxemia, we studied the expression and physiological effects of Kir6.1 in murine endotoxemic lungs. We hypothesized that inhibition of overexpressed Kir6.1 increases HPV in endotoxemia.MethodsMice (C57BL/6; n = 55) with (n = 27) and without (n = 28) endotoxemia (35 mg/kg LPS i.p. for 18 h) were analyzed for Kir6.1 gene as well as protein expression and HPV was examined in isolated perfused mouse lungs with and without selective inhibition of Kir6.1 with PNU-37883A. Pulmonary artery pressure (PAP) and pressure-flow curves during normoxic (FiO2 0.21) and hypoxic (FiO2 0.01) ventilation were obtained. HPV was quantified as the increase in perfusion pressure in response to hypoxic ventilation in mmHg of baseline perfusion pressure (ΔPAP) in the presence and absence of PNU-37883A.ResultsEndotoxemia increases pulmonary Kir6.1 gene (+ 2.8 ± 0.3-fold) and protein expression (+ 2.1 ± 0.3-fold). Hypoxia increases HPV in lungs of control animals, while endotoxemia decreases HPV (∆PAP control: 9.2 ± 0.9 mmHg vs. LPS: 3.0 ± 0.7 mmHg, p < 0.05, means ± SEM). Inhibition of Kir6.1 with 1 μM PNU-37883A increases HPV in endotoxemia, while not increasing HPV in controls (∆PAP PNU control: 9.3 ± 0.7 mmHg vs. PNU LPS: 8.3 ± 0.9 mmHg, p < 0.05, means ± SEM).ConclusionEndotoxemia increases pulmonary Kir6.1 gene and protein expression. Inhibition of Kir6.1 augments HPV in murine endotoxemic lungs.
Highlights
ATP-regulated potassium channels (KATP) regulate pulmonary vascular tone and are involved in hypoxic pulmonary vasoconstriction (HPV)
Endotoxemia increases pulmonary Kir6.1 gene expression Mice exposed to 35 mg/kg LPS i.p. showed an increase of Kir6.1 gene expression in total lung tissue extracts (2.8 ± 0.3-fold, n = 9, p < 0.05) (Fig. 1) after 18 h when compared to normal saline treated controls
These results suggest that endotoxemia increases RNA expression of the ATP-dependent potassium channel Kir6.1
Summary
ATP-regulated potassium channels (KATP) regulate pulmonary vascular tone and are involved in hypoxic pulmonary vasoconstriction (HPV). Hypoxic pulmonary vasoconstriction (HPV) is a physiological reflex, reducing intrapulmonary shunt. It is impaired in patients with sepsis or acute respiratory distress syndrome (ARDS), resulting in a ventilationperfusion mismatch and systemic hypoxia. The channel is built by an octameric protein complex consisting four pore-forming Kir6.1 units surrounded by four sulfonylurea receptor subunits (SURs). These SURs present binding sites for inhibitors like glibenclamid or PNU-99963, while the pore forming units can be blocked by barium chloride or the vascular selective KATP channel inhibitor, PNU-37883A [6, 9]
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