title: Negative inotropic effects of epinephrine in the presence of increased β-adrenoceptor sensitivity during hypothermia in a rat model.
abstract: BACKGROUND
  Animal studies show reduced inotropic effects of cardiac β-adrenoceptor agonists like epinephrine (Epi) during hypothermia and rewarming, while drugs targeting other pharmacological mechanisms have positive effects. This study therefore aimed to determine β-adrenoceptor sensitivity in isolated cardiomyocytes and investigate hemodynamic effects of Epi and its ability to stimulate cardiac β-adrenoceptors at different temperatures in vivo.
  
  
  METHODS
  Isolated rat myocardial cells were incubated with the radioactive β-adrenoceptor ligand [(3)H]-CGP12177 and propranolol, used as a displacer. Cells were subjected to normothermia (37 °C) or hypothermia (15 °C). After incubation, radioactivity was measured to estimate β-adrenoceptor affinity for propranolol (IC50), as a measure of β-adrenoceptor sensitivity. In separate in vivo experiments, Epi (1.25 μg/min) was administered the last 5min of experiments in normothermic (37 °C, 5h), hypothermic (4h at 15 °C) and rewarmed rats (4h at 15 °C, and subsequently rewarmed to 37 °C). Hemodynamic parameters were monitored during infusion. Hearts were thereafter freeze-clamped and tissue cAMP was measured.
  
  
  RESULTS
  In vitro measurements of IC50 for propranolol showed a hypothermia-induced increase in β-adrenoceptor sensitivity at 15 °C. Corresponding in vivo experiments at 15 °C showed decreased cardiac output and stroke volume, whereas total peripheral resistance (TPR) increased during Epi infusion, simultaneous with a 4-fold cAMP increase.
  
  
  CONCLUSIONS
  This experiment shows a hypothermia-induced in vivo and in vitro increase of cardiac β-adrenoceptor sensitivity, and simultaneous lack of inotropic effects of Epi in the presence of increased TPR. Our findings therefore indicate that hypothermia-induced reduction in inotropic effects of Epi is due to substantial elevation of TPR, rather than β-adrenoceptor dysfunction.
authors.affiliation: Department of Research and Education, Norwegian Air Ambulance Foundation, 1441 Drøbak, Norway; Anesthesia and Critical Care Research Group, Department 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, Department of Clinical Medicine, UiT, The Arctic University of Norway, 9037 Tromsø, Norway. Electronic address: torstein.schanche@gmail.com.
authors.forename: Torstein
authors.initials: T
authors.lastname: Schanche
authors.affiliation: Anesthesia and Critical Care Research Group, Department 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: Anesthesia and Critical Care Research Group, Department of Clinical Medicine, UiT, The Arctic University of Norway, 9037 Tromsø, Norway. Electronic address: svein.e.gaustad@ntnu.no.
authors.forename: Svein Erik
authors.initials: SE
authors.lastname: Gaustad
authors.affiliation: Medical Pharmacology and Toxicology, Department of Medical Biology, UiT, The Arctic University of Norway, 9037 Tromsø, Norway. Electronic address: georg.sager@uit.no.
authors.forename: Georg
authors.initials: G
authors.lastname: Sager
authors.affiliation: Anesthesia and Critical Care Research Group, Department 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: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004837:Epinephrine / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D007035:Hypothermia / Q000503:physiopathology*; D007036:Hypothermia, Induced; D008297:Male; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000378:metabolism*; D017694:Rewarming; D013318:Stroke Volume / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects*
chemical_list: D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D011941:Receptors, Adrenergic; D011433:Propranolol; D004837:Epinephrine
keywords: Accidental hypothermia; Adrenaline; Adrenoceptor; Afterload; Beta-receptor; Epinephrine; Hypothermia; IC(50); Inotropic treatment; cAMP