{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T21:44:12Z","timestamp":1783028652928,"version":"3.54.6"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T00:00:00Z","timestamp":1657670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> 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\u00b0C, 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.<\/jats:p><jats:p><jats:bold>Materials and methods:<\/jats:bold> The effect of PDE3 inhibitors were studied by using recombinant phosphodiesterase enzymes and inverted erythrocyte membranes at six different temperatures\u201437\u00b0C, 34\u00b0C, 32\u00b0C, 28\u00b0C, 24\u00b0C, and 20\u00b0C- 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 IC<jats:sub>50<\/jats:sub> and Ki values.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Milrinone IC<jats:sub>50<\/jats:sub> and Ki values for cGMP efflux were significantly lower at 24\u00b0C (IC<jats:sub>50<\/jats:sub>: 8.62 \u00b1 2.69\u00a0\u00b5M) and 20\u00b0C (IC<jats:sub>50<\/jats:sub>: 7.35 \u00b1 3.51\u00a0\u00b5M), compared to 37\u00b0C (IC<jats:sub>50<\/jats:sub>: 22.84 \u00b1 1.52\u00a0\u00b5M). There were no significant changes in IC<jats:sub>50<\/jats:sub> and Ki values for enzymatic breakdown of cAMP and cGMP.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Milrinone, amrinone and levosimendan, were all able to suppress enzymatic degradation and inhibit extrusion of cGMP and cAMP below 30\u00b0C. 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.<\/jats:p>","DOI":"10.3389\/fphys.2022.923091","type":"journal-article","created":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T07:44:55Z","timestamp":1657698295000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Treatment of Cardiovascular Dysfunction with PDE3-Inhibitors in Moderate and Severe Hypothermia\u2014Effects on Cellular Elimination of Cyclic Adenosine Monophosphate and Cyclic Guanosine Monophosphate"],"prefix":"10.3389","volume":"13","author":[{"given":"Adrina Kalasho","family":"Kuzmiszyn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders Lund","family":"Selli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Smaglyukova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timofei","family":"Kondratiev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole-Martin","family":"Fuskev\u00e5g","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy Andre","family":"Lys\u00e5","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aina Westrheim","family":"Ravna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torkjel","family":"Tveita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Sager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik Sveberg","family":"Dietrichs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1161\/01.cir.13.6.909","article-title":"Posthypothermic Circulatory Failure","volume":"13","author":"Blair","year":"1956","journal-title":"Circulation"},{"key":"B2","doi-asserted-by":"publisher","first-page":"4045","DOI":"10.1016\/0006-2952(84)90019-4","article-title":"Beta Adrenoceptors of Human Red Blood Cells, Determination of Their Subtypes","volume":"33","author":"Bree","year":"1984","journal-title":"Biochem. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1930","DOI":"10.1136\/bmj.1.5489.739-b10.1056\/nejmra1114208","article-title":"Accidental Hypothermia","volume":"367","author":"Brown","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3099","DOI":"10.1016\/0006-2952(73)90196-2","article-title":"Relationship between the Inhibition Constant (K1) and the Concentration of Inhibitor Which Causes 50 Per Cent Inhibition (I50) of an Enzymatic Reaction","volume":"22","author":"Cheng","year":"1973","journal-title":"Biochem. Pharmacol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/0022-5193(76)90169-7","article-title":"Derivation and Properties of Michaelis-Menten Type and Hill Type Equations for Reference Ligands","volume":"59","author":"Chou","year":"1976","journal-title":"J. Theor. Biol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1016\/j.cryobiol.2014.09.007","article-title":"Cardiovascular Effects of Levosimendan during Rewarming from Hypothermia in Rat","volume":"69","author":"Dietrichs","year":"","journal-title":"Cryobiology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.cryobiol.2014.09.002","article-title":"Milrinone Ameliorates Cardiac Mechanical Dysfunction after Hypothermia in an Intact Rat Model","volume":"69","author":"Dietrichs","year":"","journal-title":"Cryobiology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1186\/s13049-016-0339-8","article-title":"Altered Pharmacological Effects of Adrenergic Agonists during Hypothermia","volume":"24","author":"Dietrichs","year":"2016","journal-title":"Scand. J. Trauma Resusc. Emerg. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.cryobiol.2014.10.012","article-title":"Negative Inotropic Effects of Epinephrine in the Presence of Increased \u03b2-adrenoceptor Sensitivity during Hypothermia in a Rat Model","volume":"70","author":"Dietrichs","year":"2015","journal-title":"Cryobiology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/0006-2952(61)90145-9","article-title":"A New and Rapid Colorimetric Determination of Acetylcholinesterase Activity","volume":"7","author":"Ellman","year":"1961","journal-title":"Biochem. Pharmacol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1161\/CIRCRESAHA.113.301689","article-title":"Amrinone, Forerunner of Novel Cardiotonic Agents, Caused Paradigm Shift of Heart Failure Pharmacotherapy","volume":"113","author":"Endoh","year":"2013","journal-title":"Circ. Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.resuscitation.2010.09.465","article-title":"History of Accidental Hypothermia","volume":"82","author":"Guly","year":"2011","journal-title":"Resuscitation"},{"key":"B14","doi-asserted-by":"publisher","first-page":"566388","DOI":"10.3389\/fmed.2020.566388","article-title":"Comparison between Two Pharmacologic Strategies to Alleviate Rewarming Shock: Vasodilation vs. Inodilation","volume":"7","author":"H\u00e5heim","year":"2020","journal-title":"Front. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.cryobiol.2017.05.002","article-title":"The Beneficial Hemodynamic Effects of Afterload Reduction by Sodium Nitroprusside during Rewarming from Experimental Hypothermia","volume":"77","author":"H\u00e5heim","year":"2017","journal-title":"Cryobiol. Neth."},{"key":"B16","doi-asserted-by":"publisher","first-page":"H890","DOI":"10.1152\/ajpheart.00805.2009","article-title":"Mechanisms Underlying Hypothermia-Induced Cardiac Contractile Dysfunction","volume":"298","author":"Han","year":"2010","journal-title":"Am. J. Physiology-Heart Circulatory Physiology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1006\/bcmd.2000.0299","article-title":"A Beta-2-Adrenergic Receptor Activates Adenylate Cyclase in Human Erythrocyte Membranes at Physiological Calcium Plasma Concentrations","volume":"26","author":"Horga","year":"2000","journal-title":"Blood Cells, Mol. Dis."},{"key":"B18","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1097\/00000542-200207000-00017","article-title":"High-dose Amrinone Is Required to Accelerate Rewarming from Deliberate Mild Intraoperative Hypothermia for Neurosurgical Procedures","volume":"97","author":"Inoue","year":"2002","journal-title":"Anesthesiology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"449","DOI":"10.2165\/00003088-200746060-00001","article-title":"Expression of Adenosine Triphosphate-Binding Cassette (ABC) Drug Transporters in Peripheral Blood Cells: Relevance for Physiology and Pharmacotherapy","volume":"46","author":"K\u00f6ck","year":"2007","journal-title":"Clin. Pharmacokinet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.resuscitation.2021.02.011","article-title":"European Resuscitation Council Guidelines 2021: Cardiac Arrest in Special Circumstances","volume":"161","author":"Lott","year":"2021","journal-title":"Resuscitation"},{"key":"B21","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1093\/qjmed\/95.12.775","article-title":"Pathophysiology of Accidental Hypothermia","volume":"95","author":"Mallet","year":"2002","journal-title":"QJM"},{"key":"B22","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1056\/NEJMoa2026845","article-title":"Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock","volume":"385","author":"Mathew","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.718667","article-title":"Cardiovascular Effects of Epinephrine During Experimental Hypothermia (32\u00b0C) with Spontaneous Circulation in an Intact Porcine Model","volume":"12","author":"Mohyuddin","year":"2021","journal-title":"Front. Physiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.pharmthera.2016.03.014","article-title":"Novel Approaches to Targeting PDE3 in Cardiovascular Disease","volume":"163","author":"Movsesian","year":"2016","journal-title":"Pharmacol. Ther."},{"key":"B25","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.resuscitation.2021.02.038","article-title":"Clinical Staging of Accidental Hypothermia: The Revised Swiss System","volume":"162","author":"Musi","year":"2021","journal-title":"Resuscitation"},{"key":"B26","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1161\/01.RES.0000256354.95791.f1","article-title":"Overview of PDEs and Their Regulation","volume":"100","author":"Omori","year":"2007","journal-title":"Circulation Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"501","DOI":"10.3390\/ijerph19010501","article-title":"Accidental Hypothermia: 2021 Update","volume":"19","author":"Paal","year":"2022","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"B28","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1111\/jcpt.12067","article-title":"Pharmacology of Levosimendan: Inotropic, Vasodilatory and Cardioprotective Effects","volume":"38","author":"Pathak","year":"2013","journal-title":"J. Clin. Pharm. Ther."},{"key":"B29","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1097\/EJA.0b013e328330e9a0","article-title":"Influence of Temperature on the Positive Inotropic Effect of Levosimendan, Dobutamine and Milrinone","volume":"26","author":"Rieg","year":"2009","journal-title":"Eur. J. Anaesthesiol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.jtcvs.2011.09.020","article-title":"Levosimendan Is Superior to Epinephrine in Improving Myocardial Function after Cardiopulmonary Bypass with Deep Hypothermic Circulatory Arrest in Rats","volume":"143","author":"Rungatscher","year":"2012","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.2174\/138955709788681654","article-title":"Cellular Efflux of cAMP and cGMP - a Question about Selectivity","volume":"9","author":"Sager","year":"2009","journal-title":"Mrmc"},{"key":"B32","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/0006-2952(82)90243-X","article-title":"Receptor Binding Sites for Beta-Adrenergic Ligands on Human Erythrocytes","volume":"31","author":"Sager","year":"1982","journal-title":"Biochem. Pharmacol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"695779","DOI":"10.3389\/fphys.2021.695779","article-title":"Treatment of Cardiovascular Dysfunction with PDE5-Inhibitors - Temperature Dependent Effects on Transport and Metabolism of cAMP and cGMP","volume":"12","author":"Selli","year":"2021","journal-title":"Front. Physiol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/0076-6879(74)31019-1","article-title":"[16] Preparation of Impermeable Ghosts and Inside-Out Vesicles from Human Erythrocyte Membranes","volume":"31","author":"Steck","year":"1974","journal-title":"Methods Enzym."},{"key":"B35","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1111\/j.1469-7793.1999.0781u.x","article-title":"\u03b2\u2010Adrenergic Agonists Regulate Cell Membrane Fluctuations of Human Erythrocytes","volume":"516","author":"Tuvia","year":"1999","journal-title":"J. Physiology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cryobiol.2012.03.007","article-title":"Effects of Milrinone on Left Ventricular Cardiac Function during Cooling in an Intact Animal Model","volume":"65","author":"Tveita","year":"2012","journal-title":"Cryobiology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1152\/jappl.1996.80.1.291","article-title":"Experimental Hypothermia and Rewarming: Changes in Mechanical Function and Metabolism of Rat Hearts","volume":"80","author":"Tveita","year":"1996","journal-title":"J. Appl. Physiology"},{"key":"B3","doi-asserted-by":"crossref","first-page":"277","DOI":"10.2165\/11319360-000000000-00000","article-title":"Effects of Hypothermia on Pharmacokinetics and Pharmacodynamics: a Systematic Review of Preclinical and Clinical Studies","volume":"49","author":"van den Broek","year":"2010","journal-title":"Clin. Pharmacokinet."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1550","DOI":"10.1016\/j.resuscitation.2010.05.023","article-title":"Accidental Hypothermia: Rewarming Treatments, Complications and Outcomes from One University Medical Centre","volume":"81","author":"Van der Ploeg","year":"2010","journal-title":"Resuscitation"},{"key":"B39","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1186\/1479-7364-3-3-281","article-title":"Human ATP-Binding Cassette (ABC) Transporter Family","volume":"3","author":"Vasiliou","year":"2008","journal-title":"Hum. Genomics"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1998","DOI":"10.1378\/chest.120.6.1998","article-title":"Severe Accidental Hypothermia Treated in an ICU","volume":"120","author":"Vassal","year":"2001","journal-title":"Chest"},{"key":"B41","doi-asserted-by":"publisher","first-page":"3715","DOI":"10.3892\/mmr.2016.5005","article-title":"The Cyclic AMP Signaling Pathway: Exploring Targets for Successful Drug Discovery (Review)","volume":"13","author":"Yan","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"B42","doi-asserted-by":"publisher","first-page":"158","DOI":"10.2165\/00003495-198836020-00003","article-title":"Milrinone","volume":"36","author":"Young","year":"1988","journal-title":"Drugs"}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2022.923091\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T07:44:58Z","timestamp":1657698298000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2022.923091\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,13]]},"references-count":42,"alternative-id":["10.3389\/fphys.2022.923091"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2022.923091","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,13]]},"article-number":"923091"}}