title: The effects of hyperoxia on the biosynthesis of cyclooxygenase products and haemodynamic response to nitric oxide synthase inhibition with L-NAME in endotoxaemic pigs.
abstract: The interaction between constitutive nitric oxide and oxygen may depend on the degree of tissue oxygenation and may play a critical role in the pathophysiological response to endotoxaemia. We investigated if hyperoxia (100% O2) attenuated the systemic and pulmonary vasoconstriction and increased biosynthesis of thromboxane B2 (TXB2) and 6-keto-prostaglandin (PG) F1alpha induced by inhibition of nitric oxide synthase with NG-nitro-L-arginine-methyl-ester (L-NAME) in a porcine model of endotoxaemia. Twenty-two domestic, random source pigs, weighing 15.4 +/- 2.7 kg (mean +/- standard deviation) were the subjects of this study. Pigs were anaesthetized with isoflurane in 100% O2, orotracheally intubated and ventilated to maintain normocapnia, and then instrumented for haemodynamic monitoring. Following instrumentation, pigs were maintained at an end-tidal isoflurane concentration of 2%. Pigs were randomly assigned to treatment groups: saline + 30% O2 (Control, n = 6); Escherichia coli lipopolysaccharide (5 microg/kg/h from 1 to 2 h followed by 2 microg/kg/h from 2 to 5 h) + 30% O2 (LPS, n = 4); L-NAME (0.5 mg/kg/h, from 0 to 5 h) + LPS + 100% O2 (n = 6); and L-NAME + LPS + 30% O2 (n = 6). L-NAME and endotoxin significantly (P < 0.05) increased mean arterial pressure, mean pulmonary arterial pressure, and systemic and pulmonary vascular resistance index beginning at 90 min. When results were pooled across all time periods, mean arterial pressure and mean pulmonary arterial pressure were significantly higher in the L-NAME + LPS + 30% O2 group than all other groups, reflecting pulmonary and systemic vasoconstriction. Hyperoxia attenuated the L-NAME + LPS-induced increases in TXB2 and 6-keto-PGF1alpha concentrations at 90 and 120 min and 120 min, respectively, although the differences were not statistically significant. These results support the observation that nitric oxide synthase inhibition with L-NAME has deleterious haemodynamic effects in this model of endotoxaemia. The temporal attenuation of L-NAME-induced pulmonary and systemic vasoconstriction by hyperoxia suggested that the haemodynamic effects of acute endotoxaemia were in part influenced by the relative amounts of nitric oxide and oxygen present.
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins 80523, USA.
authors.forename: P W
authors.initials: PW
authors.lastname: Hellyer
authors.forename: B
authors.initials: B
authors.lastname: Wright
authors.forename: C
authors.initials: C
authors.lastname: Mallinckrodt
authors.forename: J S
authors.initials: JS
authors.lastname: Gaynor
authors.forename: K R
authors.initials: KR
authors.lastname: Mama
authors.forename: A E
authors.initials: AE
authors.lastname: Wagner
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis*; D000818:Animals; D019446:Endotoxemia / Q000503:physiopathology / Q000662:veterinary*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004927:Escherichia coli Infections / Q000503:physiopathology / Q000662:veterinary*; D006439:Hemodynamics; D018496:Hyperoxia / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply* / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D011652:Pulmonary Circulation / Q000187:drug effects; D013552:Swine; D013553:Swine Diseases / Q000382:microbiology* / Q000503:physiopathology; D013929:Thromboxane B2 / Q000096:biosynthesis*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester