Selective inhibition of guanylate cyclase prevents impairment of hypoxic pulmonary vasoconstriction in endotoxemic mice.
Nitric oxide (NO) may cause sepsis-induced impairment of hypoxic pulmonary vasoconstriction (HPV). Although NO exerts many of its actions by activating soluble guanylate cyclase (sGC), there are several cGC-independent mechanisms that may lead to NO-induced vasodilation during endotoxemia. We investigated the role of sGC for the regulation of HPV during lipopolysaccharide (LPS) induced endotoxemia using 1H-(1,2,4)oxadiazole(4,3-alpha)quinoxaline-1-one (ODQ), a specific inhibitor of sGC, in isolated, perfused, and ventilated mouse lungs. Without ODQ, lungs from LPS-challenged mice constricted significantly less in response to hypoxia as compared to lungs from mice not treated with LPS (26 +/- 27% vs. 134 +/- 37%, respectively, p < 0.05). 20 mg/kg ODQ, but not 2 mg/kg or 10 mg/kg, restored the blunted HPV response in LPS-challenged mice as compared to mice not challenged with LPS (80+/-14 % vs. 98+/-21 %). ODQ had no effect on baseline perfusion pressures under normoxic conditions. Analysis of pulmonary vascular P-Q relationships suggested that the restoration of pulmonary vascular response to hypoxia by ODQ is associated with a restoration of pulmonary vascular properties during normoxia. Our data show in a murine model that specific inhibition of sGC may be a new approach to restore HPV during endotoxemia.
Spohr
F
F
Department of Anaesthesiology and Postoperative Intensive Care Medicine, University of Cologne, Cologne, Germany.
Busch
C J
CJ
Teschendorf
P
P
Weimann
J
J
D000818:Animals; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000503:physiopathology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors*; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000098:blood supply / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010069:Oxadiazoles / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D008070:Lipopolysaccharides; D010069:Oxadiazoles; D011810:Quinoxalines; D006162:Guanylate Cyclase