Treatment of Cardiovascular Dysfunction with PDE3-Inhibitors in Moderate and Severe Hypothermia—Effects on Cellular Elimination of Cyclic Adenosine Monophosphate and Cyclic Guanosine Monophosphate
Introduction: Rewarming from accidental hypothermia is often complicated by hypothermia-induced cardiovascular dysfunction, which could lead to shock. Current guidelines do not recommend any pharmacological treatment at core temperatures below 30°C, due to lack of knowledge. However, previous in viv...
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.923091/full |
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| author | Adrina Kalasho Kuzmiszyn Adrina Kalasho Kuzmiszyn Adrina Kalasho Kuzmiszyn Anders Lund Selli Natalia Smaglyukova Timofei Kondratiev Ole-Martin Fuskevåg Roy Andre Lyså Aina Westrheim Ravna Torkjel Tveita Torkjel Tveita Georg Sager Erik Sveberg Dietrichs Erik Sveberg Dietrichs |
| author_facet | Adrina Kalasho Kuzmiszyn Adrina Kalasho Kuzmiszyn Adrina Kalasho Kuzmiszyn Anders Lund Selli Natalia Smaglyukova Timofei Kondratiev Ole-Martin Fuskevåg Roy Andre Lyså Aina Westrheim Ravna Torkjel Tveita Torkjel Tveita Georg Sager Erik Sveberg Dietrichs Erik Sveberg Dietrichs |
| author_sort | Adrina Kalasho Kuzmiszyn |
| collection | DOAJ |
| description | Introduction: Rewarming from accidental hypothermia is often complicated by hypothermia-induced cardiovascular dysfunction, which could lead to shock. Current guidelines do not recommend any pharmacological treatment at core temperatures below 30°C, due to lack of knowledge. However, previous in vivo studies have shown promising results when using phosphodiesterase 3 (PDE3) inhibitors, which possess the combined effects of supporting cardiac function and alleviating the peripheral vascular resistance through changes in cyclic nucleotide levels. This study therefore aims to investigate whether PDE3 inhibitors milrinone, amrinone, and levosimendan are able to modulate cyclic nucleotide regulation in hypothermic settings.Materials and methods: The effect of PDE3 inhibitors were studied by using recombinant phosphodiesterase enzymes and inverted erythrocyte membranes at six different temperatures—37°C, 34°C, 32°C, 28°C, 24°C, and 20°C- in order to evaluate the degree of enzymatic degradation, as well as measuring cellular efflux of both cAMP and cGMP. The resulting dose-response curves at every temperature were used to calculate IC50 and Ki values.Results: Milrinone IC50 and Ki values for cGMP efflux were significantly lower at 24°C (IC50: 8.62 ± 2.69 µM) and 20°C (IC50: 7.35 ± 3.51 µM), compared to 37°C (IC50: 22.84 ± 1.52 µM). There were no significant changes in IC50 and Ki values for enzymatic breakdown of cAMP and cGMP.Conclusion: Milrinone, amrinone and levosimendan, were all able to suppress enzymatic degradation and inhibit extrusion of cGMP and cAMP below 30°C. Our results show that these drugs have preserved effect on their target molecules during hypothermia, indicating that they could provide an important treatment option for hypothermia-induced cardiac dysfunction. |
| first_indexed | 2024-04-12T09:05:39Z |
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| id | doaj.art-218ba614aef944caa6c5b774dba33ce7 |
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| language | English |
| last_indexed | 2024-04-12T09:05:39Z |
| publishDate | 2022-07-01 |
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| series | Frontiers in Physiology |
| spelling | doaj.art-218ba614aef944caa6c5b774dba33ce72022-12-22T03:39:06ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-07-011310.3389/fphys.2022.923091923091Treatment of Cardiovascular Dysfunction with PDE3-Inhibitors in Moderate and Severe Hypothermia—Effects on Cellular Elimination of Cyclic Adenosine Monophosphate and Cyclic Guanosine MonophosphateAdrina Kalasho Kuzmiszyn0Adrina Kalasho Kuzmiszyn1Adrina Kalasho Kuzmiszyn2Anders Lund Selli3Natalia Smaglyukova4Timofei Kondratiev5Ole-Martin Fuskevåg6Roy Andre Lyså7Aina Westrheim Ravna8Torkjel Tveita9Torkjel Tveita10Georg Sager11Erik Sveberg Dietrichs12Erik Sveberg Dietrichs13Norwegian Air Ambulance Foundation, Research and Development Department, Oslo, NorwayExperimental and Clinical Pharmacology, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, NorwayDivision of Surgical Medicine and Intensive Care, University Hospital of North Norway, Tromsø, NorwayExperimental and Clinical Pharmacology, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, NorwayExperimental and Clinical Pharmacology, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, NorwayAnesthesia and Critical Care Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, NorwayDepartment of Laboratory Medicine, Division of Diagnostic Services, University Hospital of North Norway, Tromsø, NorwayExperimental and Clinical Pharmacology, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, NorwayExperimental and Clinical Pharmacology, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, NorwayDivision of Surgical Medicine and Intensive Care, University Hospital of North Norway, Tromsø, NorwayAnesthesia and Critical Care Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, NorwayExperimental and Clinical Pharmacology, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, NorwayExperimental and Clinical Pharmacology, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, NorwayCenter for Psychopharmacology, Diakonhjemmet Hospital, Oslo, NorwayIntroduction: Rewarming from accidental hypothermia is often complicated by hypothermia-induced cardiovascular dysfunction, which could lead to shock. Current guidelines do not recommend any pharmacological treatment at core temperatures below 30°C, due to lack of knowledge. However, previous in vivo studies have shown promising results when using phosphodiesterase 3 (PDE3) inhibitors, which possess the combined effects of supporting cardiac function and alleviating the peripheral vascular resistance through changes in cyclic nucleotide levels. This study therefore aims to investigate whether PDE3 inhibitors milrinone, amrinone, and levosimendan are able to modulate cyclic nucleotide regulation in hypothermic settings.Materials and methods: The effect of PDE3 inhibitors were studied by using recombinant phosphodiesterase enzymes and inverted erythrocyte membranes at six different temperatures—37°C, 34°C, 32°C, 28°C, 24°C, and 20°C- in order to evaluate the degree of enzymatic degradation, as well as measuring cellular efflux of both cAMP and cGMP. The resulting dose-response curves at every temperature were used to calculate IC50 and Ki values.Results: Milrinone IC50 and Ki values for cGMP efflux were significantly lower at 24°C (IC50: 8.62 ± 2.69 µM) and 20°C (IC50: 7.35 ± 3.51 µM), compared to 37°C (IC50: 22.84 ± 1.52 µM). There were no significant changes in IC50 and Ki values for enzymatic breakdown of cAMP and cGMP.Conclusion: Milrinone, amrinone and levosimendan, were all able to suppress enzymatic degradation and inhibit extrusion of cGMP and cAMP below 30°C. Our results show that these drugs have preserved effect on their target molecules during hypothermia, indicating that they could provide an important treatment option for hypothermia-induced cardiac dysfunction.https://www.frontiersin.org/articles/10.3389/fphys.2022.923091/fullhypothermiaphosphodiesterase 3 inhibitorphosphodiesterase 3ATP-binding cassette transportercyclic AMPcyclic GMP |
| spellingShingle | Adrina Kalasho Kuzmiszyn Adrina Kalasho Kuzmiszyn Adrina Kalasho Kuzmiszyn Anders Lund Selli Natalia Smaglyukova Timofei Kondratiev Ole-Martin Fuskevåg Roy Andre Lyså Aina Westrheim Ravna Torkjel Tveita Torkjel Tveita Georg Sager Erik Sveberg Dietrichs Erik Sveberg Dietrichs Treatment of Cardiovascular Dysfunction with PDE3-Inhibitors in Moderate and Severe Hypothermia—Effects on Cellular Elimination of Cyclic Adenosine Monophosphate and Cyclic Guanosine Monophosphate Frontiers in Physiology hypothermia phosphodiesterase 3 inhibitor phosphodiesterase 3 ATP-binding cassette transporter cyclic AMP cyclic GMP |
| title | Treatment of Cardiovascular Dysfunction with PDE3-Inhibitors in Moderate and Severe Hypothermia—Effects on Cellular Elimination of Cyclic Adenosine Monophosphate and Cyclic Guanosine Monophosphate |
| title_full | Treatment of Cardiovascular Dysfunction with PDE3-Inhibitors in Moderate and Severe Hypothermia—Effects on Cellular Elimination of Cyclic Adenosine Monophosphate and Cyclic Guanosine Monophosphate |
| title_fullStr | Treatment of Cardiovascular Dysfunction with PDE3-Inhibitors in Moderate and Severe Hypothermia—Effects on Cellular Elimination of Cyclic Adenosine Monophosphate and Cyclic Guanosine Monophosphate |
| title_full_unstemmed | Treatment of Cardiovascular Dysfunction with PDE3-Inhibitors in Moderate and Severe Hypothermia—Effects on Cellular Elimination of Cyclic Adenosine Monophosphate and Cyclic Guanosine Monophosphate |
| title_short | Treatment of Cardiovascular Dysfunction with PDE3-Inhibitors in Moderate and Severe Hypothermia—Effects on Cellular Elimination of Cyclic Adenosine Monophosphate and Cyclic Guanosine Monophosphate |
| title_sort | treatment of cardiovascular dysfunction with pde3 inhibitors in moderate and severe hypothermia effects on cellular elimination of cyclic adenosine monophosphate and cyclic guanosine monophosphate |
| topic | hypothermia phosphodiesterase 3 inhibitor phosphodiesterase 3 ATP-binding cassette transporter cyclic AMP cyclic GMP |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.923091/full |
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