title: Cardiovascular effects of levosimendan during rewarming from hypothermia in rat.
abstract: BACKGROUND
  Previous research aimed at ameliorating hypothermia-induced cardiac dysfunction has shown that inotropic drugs, that stimulate the cAMP, - PKA pathway via the sarcolemmal β-receptor, have a decreased inotropic effect during hypothermia. We therefore wanted to test whether levosimendan, a calcium sensitizer and dose-dependent phosphodiesterase 3 (PDE3) inhibitor, is able to elevate stroke volume during rewarming from experimental hypothermia.
  
  
  METHODS
  A rat model designed for circulatory studies during experimental hypothermia (4h at 15°C) and rewarming was used. The following three groups were included: (1) A normothermic group receiving levosimendan, (2) a hypothermic group receiving levosimendan the last hour of stable hypothermia and during rewarming, and (3) a hypothermic placebo control group. Hemodynamic variables were monitored using a Millar conductance catheter in the left ventricle (LV), and a pressure transducer connected to the left femoral artery. In order to investigate the level of PKA stimulation by PDE3 inhibition, myocardial Ser23/24-cTnI phosphorylation was measured using Western-blot.
  
  
  RESULTS
  After rewarming, stroke volume (SV), cardiac output (CO) and preload recruitable stroke work (PRSW) were restored to within pre-hypothermic values in the levosimendan-treated animals. Compared to the placebo group after rewarming, SV, CO, PRSW, as well as levels of Ser23/24-cTnI phosphorylation, were significantly higher in the levosimendan-treated animals.
  
  
  CONCLUSIONS
  The present data shows that levosimendan ameliorates hypothermia-induced systolic dysfunction by elevating SV during rewarming from 15°C. Inotropic treatment during rewarming from hypothermia in the present rat model is therefore better achieved through calcium sensitizing and PDE3 inhibition, than β-receptor stimulation.
authors.affiliation: Dept. of Research and Education, Norwegian Air Ambulance Foundation, 1441 Drøbak, Norway; Anesthesia and Critical Care Research Group, Institute of Clinical Medicine, UiT, The Arctic University of Norway, 9037 Tromsø, Norway. Electronic address: erik.sveberg.dietrichs@norskluftambulanse.no.
authors.forename: Erik Sveberg
authors.initials: ES
authors.lastname: Dietrichs
authors.affiliation: Anesthesia and Critical Care Research Group, Institute of Clinical Medicine, UiT, The Arctic University of Norway, 9037 Tromsø, Norway; Dept. of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Electronic address: bha035@post.uit.no.
authors.forename: Brage
authors.initials: B
authors.lastname: Håheim
authors.affiliation: Anesthesia and Critical Care Research Group, Institute of Clinical Medicine, UiT, The Arctic University of Norway, 9037 Tromsø, Norway. Electronic address: timofey.kondratiev@uit.no.
authors.forename: Timofei
authors.initials: T
authors.lastname: Kondratiev
authors.affiliation: Dept. of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Anesthesia and Critical Care Research Group, Institute of Clinical Medicine, UiT, The Arctic University of Norway, 9037 Tromsø, Norway. Electronic address: sieck.gary@mayo.edu.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Sieck
authors.affiliation: Anesthesia and Critical Care Research Group, Institute of Clinical Medicine, UiT, The Arctic University of Norway, 9037 Tromsø, Norway; Division of Surgical Medicine and Intensive Care, University Hospital of North Norway, 9038 Tromsø, Norway. Electronic address: torkjel.tveita@uit.no.
authors.forename: Torkjel
authors.initials: T
authors.lastname: Tveita
mesh_terms: D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006835:Hydrazones / Q000627:therapeutic use*; D007035:Hypothermia / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D007036:Hypothermia, Induced / Q000009:adverse effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D011724:Pyridazines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017694:Rewarming / Q000009:adverse effects*; D000077464:Simendan; D013318:Stroke Volume / Q000187:drug effects; D019210:Troponin I / Q000097:blood / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D006835:Hydrazones; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D019210:Troponin I; D000077464:Simendan
keywords: Accidental hypothermia; Calcium sensitizer; Cardiovascular support; Hypothermia; Levosimendan; PDE3 inhibitor; Rewarming; Rewarming shock; Troponin I; Troponin phosphorylation