Erik Sveberg Dietrichs1, Brage Håheim2, Timofei Kondratiev3, Gary C Sieck4, Torkjel Tveita5. 1. 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. 2. 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. 3. 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. 4. 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. 5. 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.
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. CONCLUSION: 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.
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. CONCLUSION: 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: Anders L Selli; Adrina K Kuzmiszyn; Natalia Smaglyukova; Timofei V Kondratiev; Ole-Martin Fuskevåg; Roy A Lyså; Aina W Ravna; Torkjel Tveita; Georg Sager; Erik S Dietrichs Journal: Front Physiol Date: 2021-07-30 Impact factor: 4.566
Authors: Lars J Bjertnæs; Torvind O Næsheim; Eirik Reierth; Evgeny V Suborov; Mikhail Y Kirov; Konstantin M Lebedinskii; Torkjel Tveita Journal: Front Med (Lausanne) Date: 2022-02-23
Authors: Adrina Kalasho Kuzmiszyn; Anders Lund Selli; Natalia Smaglyukova; Timofei Kondratiev; Ole-Martin Fuskevåg; Roy Andre Lyså; Aina Westrheim Ravna; Torkjel Tveita; Georg Sager; Erik Sveberg Dietrichs Journal: Front Physiol Date: 2022-07-13 Impact factor: 4.755