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 invest...

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Bibliographic Details
Published inJournal of physiology and pharmacology : an official journal of the Polish Physiological Society Vol. 60; no. 2; p. 107
Main Authors Spohr, F, Busch, C J, Teschendorf, P, Weimann, J
Format Journal Article
LanguageEnglish
Published Poland 01.06.2009
Subjects
Animals
Dose-Response Relationship, Drug
Endotoxemia - physiopathology
Guanylate Cyclase - antagonists & inhibitors
Hypoxia - physiopathology
In Vitro Techniques
Lipopolysaccharides - pharmacology
Lung - blood supply
Lung - drug effects
Male
Mice
Mice, Inbred C57BL
Oxadiazoles - pharmacology
Pulmonary Circulation - drug effects
Pulmonary Circulation - physiology
Quinoxalines - pharmacology
Vasoconstriction - drug effects
Vasoconstriction - physiology
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Summary: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.
ISSN:1899-1505