title: Nitric oxide inhibition in the treatment of the sepsis syndrome is detrimental to tissue oxygenation.
abstract: The manifestations of the septic syndrome are thought to be mediated by cytokines through their role in the production of nitric oxide (NO). It is hypothesized that the inhibition of NO production with an inhibitor such as NG-monomethyl-L-arginine (L-NMMA) may be beneficial in the treatment of septic shock. Sepsis was induced by the intravenous administration of Escherichia coli endotoxin (60 micrograms/kg) in six conditioned mongrel dogs (20-24 kg). Mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), and pulmonary artery pressure (PAP) were continuously monitored. Cardiac output (CO), pulmonary capillary wedge pressure (PCWP), and arterial and mixed venous blood gases were obtained every 10 min. When the MAP decreased below 60 mm Hg, NO inhibitor L-NMMA was given by intravenous injection (25 mg/kg). Physiologic parameters were then measured at 2 and 5 min after L-NMMA injection. Subsequently, L-arginine (400 mg/kg), the substrate for the NO synthase enzyme, was administered and measurements were repeated at similar intervals. L-NMMA in septic canines produced a significant increase in MAP and SVR with a significant decrease in CO and tissue oxygenation (DO2 and VO2). These changes were reversed with the administration of L-arginine. There were no significant differences in the PCWP, CVP, PAP, or HR throughout the entire study. These results suggest that the inhibition of NO production by L-NMMA in a septic model produces elevated MAP and SVR at the expense of tissue oxygenation. Thus, its use, as a principal means of therapy for the septic syndrome, may not be appropriate because of detrimental effects on tissue oxygenation.
authors.affiliation: Department of Surgery, Maimonides Medical Center, S.U.N.Y. Health Science Center at Brooklyn 11219.
authors.forename: R
authors.initials: R
authors.lastname: Statman
authors.forename: W
authors.initials: W
authors.lastname: Cheng
authors.forename: J N
authors.initials: JN
authors.lastname: Cunningham
authors.forename: J L
authors.initials: JL
authors.lastname: Henderson
authors.forename: P
authors.initials: P
authors.lastname: Damiani
authors.forename: A
authors.initials: A
authors.lastname: Siconolfi
authors.forename: D
authors.initials: D
authors.lastname: Rogers
authors.forename: J H
authors.initials: JH
authors.lastname: Horovitz
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D004731:Endotoxins / Q000494:pharmacology; D004927:Escherichia coli Infections / Q000188:drug therapy*; D006439:Hemodynamics / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D010101:Oxygen Consumption / Q000187:drug effects*; D013577:Syndrome; D014655:Vascular Resistance / Q000187:drug effects; D019323:omega-N-Methylarginine
chemical_list: D004731:Endotoxins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine