title: Role of inducible nitric oxide synthase in the reduced responsiveness of the myocardium to catecholamines in a hyperdynamic, murine model of septic shock.
abstract: OBJECTIVE
  Excess nitric oxide production is a key mediator of hypotension and catecholamine-resistance in septic shock. Although nitric oxide synthase blockade has been shown to restore hemodynamics, conflicting results on myocardial function were reported. Inducible nitric oxide synthase (iNOS) knockout (iNOS-/-) mice showed improved heart function, but these results were obtained during hypodynamic shock characterized by reduced cardiac output. Therefore, we investigated heart function and catecholamine responsiveness in a clinically relevant, murine model of cecal ligation and puncture (CLP)-induced septic shock.
  
  
  METHODS
  Prospective, controlled, randomized animal study.
  
  
  METHODS
  University animal research laboratory.
  
  
  METHODS
  Male C57Bl/6 wild-type and iNOS-/- mice.
  
  
  METHODS
  Fifteen hours after CLP, three groups of mice (wild-type controls, n = 9; iNOS-/-, n = 12; and wild-type mice receiving 5 mg x kg(-1) intraperitoneally of the selective iNOS inhibitor GW274150 immediately after CLP, n = 8) were anesthetized, mechanically ventilated, and instrumented (central venous and left ventricular pressure-conductance catheter). Measurements were recorded 18, 21, and 24 hrs post-CLP. Hydroxyethylstarch and norepinephrine were infused to achieve normotensive and hyperdynamic hemodynamics.
  
  
  RESULTS
  There was no intergroup difference in mean arterial pressure, stroke volume, and left ventricular ejection fraction. Norepinephrine doses required to achieve the hemodynamic targets were lower in GW274150 (p < .001 vs. controls) and even further reduced in iNOS-/- mice (p < .001 vs. controls, p < .001 vs. GW274150). In the control group, the higher norepinephrine doses resulted in significantly higher heart rates and consequently cardiac output, maximal contraction, and relaxation than in the GW274150 and iNOS-/- animals. Left ventricular end-diastolic volume was also significantly higher in the controls than in the GW274150 and iNOS-/- mice, whereas left ventricular end-diastolic pressure did not differ.
  
  
  CONCLUSIONS
  Our results confirm septic shock-related impaired left ventricular function. Genetic iNOS deletion and pharmacologic iNOS blockade enhanced cardiac norepinephrine responsiveness due to improved systolic function. In contrast, iNOS inhibition seemed to be affiliated with compromised left ventricular relaxation.
authors.affiliation: Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum, Ulm, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Barth
authors.forename: Peter
authors.initials: P
authors.lastname: Radermacher
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
authors.forename: Sandra
authors.initials: S
authors.lastname: Weber
authors.forename: Michael
authors.initials: M
authors.lastname: Georgieff
authors.forename: Gerd
authors.initials: G
authors.lastname: Albuszies
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005440:Fluid Therapy; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D009638:Norepinephrine / Q000494:pharmacology*; D012772:Shock, Septic / Q000378:metabolism / Q000628:therapy*; D013440:Sulfides / Q000494:pharmacology*
chemical_list: D013440:Sulfides; C409004:GW 274150; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D009638:Norepinephrine