title: Norepinephrine to increase blood pressure in endotoxaemic pigs is associated with improved hepatic mitochondrial respiration.
abstract: BACKGROUND
  Low blood pressure, inadequate tissue oxygen delivery and mitochondrial dysfunction have all been implicated in the development of sepsis-induced organ failure. This study evaluated the effect on liver mitochondrial function of using norepinephrine to increase blood pressure in experimental sepsis.
  
  
  METHODS
  Thirteen anaesthetized pigs received endotoxin (Escherichia coli lipopolysaccharide B0111:B4; 0.4 microg/kg per hour) and were subsequently randomly assigned to norepinephrine treatment or placebo for 10 hours. Norepinephrine dose was adjusted at 2-hour intervals to achieve 15 mmHg increases in mean arterial blood pressure up to 95 mmHg. Systemic (thermodilution) and hepatosplanchnic (ultrasound Doppler) blood flow were measured at each step. At the end of the experiment, hepatic mitochondrial oxygen consumption (high-resolution respirometry) and citrate synthase activity (spectrophotometry) were assessed.
  
  
  RESULTS
  Mean arterial pressure (mmHg) increased only in norepinephrine-treated animals (from 73 [median; range 69 to 81] to 63 [60 to 68] in controls [P = 0.09] and from 83 [69 to 93] to 96 [86 to 108] in norepinephrine-treated animals [P = 0.019]). Cardiac index and systemic oxygen delivery (DO2) increased in both groups, but significantly more in the norepinephrine group (P < 0.03 for both). Cardiac index (ml/min per kg) increased from 99 (range: 72 to 112) to 117 (110 to 232) in controls (P = 0.002), and from 107 (84 to 132) to 161 (147 to 340) in norepinephrine-treated animals (P = 0.001). DO2 (ml/min per kg) increased from 13 (range: 11 to 15) to 16 (15 to 24) in controls (P = 0.028), and from 16 (12 to 19) to 29 (25 to 52) in norepinephrine-treated animals (P = 0.018). Systemic oxygen consumption (systemic VO2) increased in both groups (P < 0.05), whereas hepatosplanchnic flows, DO2 and VO2 remained stable. The hepatic lactate extraction ratio decreased in both groups (P = 0.05). Liver mitochondria complex I-dependent and II-dependent respiratory control ratios were increased in the norepinephrine group (complex I: 3.5 [range: 2.1 to 5.7] in controls versus 5.8 [4.8 to 6.4] in norepinephrine-treated animals [P = 0.015]; complex II: 3.1 [2.3 to 3.8] in controls versus 3.7 [3.3 to 4.6] in norepinephrine-treated animals [P = 0.09]). No differences were observed in citrate synthase activity.
  
  
  CONCLUSIONS
  Norepinephrine treatment during endotoxaemia does not increase hepatosplanchnic flow, oxygen delivery or consumption, and does not improve the hepatic lactate extraction ratio. However, norepinephrine increases the liver mitochondria complex I-dependent and II-dependent respiratory control ratios. This effect was probably mediated by a direct effect of norepinephrine on liver cells.
authors.affiliation: Experimental Surgical Unit, Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Tomas
authors.initials: T
authors.lastname: Regueira
authors.forename: Bertram
authors.initials: B
authors.lastname: Bänziger
authors.forename: Siamak
authors.initials: S
authors.lastname: Djafarzadeh
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandt
authors.forename: Jose
authors.initials: J
authors.lastname: Gorrasi
authors.forename: Jukka
authors.initials: J
authors.lastname: Takala
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Lepper
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Jakob
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D019446:Endotoxemia / Q000188:drug therapy / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology* / Q000627:therapeutic use; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D034421:Sus scrofa; D013552:Swine
chemical_list: D009638:Norepinephrine