title: Endotoxin stuns cGMP-mediated pulmonary vasorelaxation.
abstract: Net pulmonary vascular tone is determined by the balance of pulmonary vasorelaxation and vasoconstriction. In endotoxemic rats, cGMP-mediated pulmonary vasorelaxation is impaired through neutrophil-dependent mechanisms, yet agonist stimulated vasoconstriction remains intact. Endotoxin-induced lung neutrophil accumulation is a transient response. In models of myocardial ischemia-reperfusion injury, "stunning" or reversible cardiac dysfunction is also associated with a reversible neutrophil presence. We hypothesized that lung neutrophil accumulation and dysfunction of cGMP-mediated pulmonary vasorelaxation is reversible after an endotoxin challenge. Our purpose was to examine lung neutrophil accumulation and endothelium-dependent and -independent mechanisms of cGMP-mediated pulmonary vasorelaxation 4 and 48 h after endotoxin challenge. Rats (n = 5 per group) were studied 4 and 48 h after injection of saline or endotoxin (500 micrograms/kg, intraperitoneal). Endothelium-dependent relaxation by receptor-dependent (acetylcholine) and -independent (A23187) mechanisms and endothelium-independent (sodium nitroprusside) relaxation were studied in isolated pulmonary artery rings preconstricted with phenylephrine. Lung neutrophil accumulation was examined by lung myeloperoxidase assay. Lung neutrophil accumulation was increased at 4 h (p < .05 vs. control) and was attenuated by 48 h (p < .05 vs. endotoxin x 4 h) following endotoxin challenge. Similarly, the endotoxin-induced dysfunction of endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation at 4 h normalized by 48 h. Endotoxin appears to induce reversible dysfunction of pulmonary vasorelaxation through stunning of vascular endothelial and smooth muscle cells.
authors.affiliation: Department of Surgery, University of Colorado, Denver 80262, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Sheridan
authors.forename: R C
authors.initials: RC
authors.lastname: McIntyre
authors.forename: D R
authors.initials: DR
authors.lastname: Meldrum
authors.forename: X
authors.initials: X
authors.lastname: Meng
authors.forename: D A
authors.initials: DA
authors.lastname: Fullerton
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004731:Endotoxins / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D004731:Endotoxins; D009599:Nitroprusside; D000001:Calcimycin; D009195:Peroxidase; D006152:Cyclic GMP; D000109:Acetylcholine