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dc.contributor.authorSelli, Anders Lund
dc.contributor.authorKuzmiszyn, Adrina Kalasho
dc.contributor.authorSmaglyukova, Natalia
dc.contributor.authorKondratiev, Timofei V.
dc.contributor.authorFuskevåg, Ole Martin
dc.contributor.authorLyså, Roy Andre
dc.contributor.authorRavna, Aina Westrheim
dc.contributor.authorTveita, Torkjel
dc.contributor.authorSager, Georg
dc.contributor.authorDietrichs, Erik Sveberg
dc.date.accessioned2021-09-23T07:58:08Z
dc.date.available2021-09-23T07:58:08Z
dc.date.issued2021-07-30
dc.description.abstract<i>Introduction</i>: Cardiovascular dysfunction is a potentially lethal complication of hypothermia. Due to a knowledge gap, pharmacological interventions are not recommended at core temperatures below 30°C. Yet, further cooling is induced in surgical procedures and survival of accidental hypothermia is reported after rewarming from below 15°C, advocating a need for evidence-based treatment guidelines. In vivo studies have proposed vasodilation and afterload reduction through arteriole smooth muscle cGMP-elevation as a favorable strategy to prevent cardiovascular dysfunction in hypothermia. Further development of treatment guidelines demand information about temperature-dependent changes in pharmacological effects of clinically relevant vasodilators.<br><br> <i>Materials and Methods</i>: Human phosphodiesterase-enzymes and inverted erythrocytes were utilized to evaluate how vasodilators sildenafil and vardenafil affected cellular efflux and enzymatic breakdown of cAMP and cGMP, at 37°C, 34°C, 32°C, 28°C, 24°C, and 20°C. The ability of both drugs to reach their cytosolic site of action was assessed at the same temperatures. IC<sub>50</sub>- and K<sub>i</sub>-values were calculated from dose–response curves at all temperatures, to evaluate temperature-dependent effects of both drugs.<br><br> <i>Results</i>: Both drugs were able to reach the intracellular space at all hypothermic temperatures, with no reduction compared to normothermia. Sildenafil IC<sub>50</sub> and K<sub>i</sub>-values increased during hypothermia for enzymatic breakdown of both cAMP (IC<sub>50</sub>: 122 ± 18.9 μM at 37°C vs. 269 ± 14.7 μM at 20°C, <i>p</i> < 0.05) and cGMP (IC<sub>50</sub>: 0.009 ± 0.000 μM at 37°C vs. 0.024 ± 0.004 μM at 32°C, <i>p</i> < 0.05), while no significant changes were detected for vardenafil. Neither of the drugs showed significant hypothermia-induced changes in IC<sub>50</sub> and K<sub>i</sub>–values for inhibition of cellular cAMP and cGMP efflux.<br><br> <i>Conclusion</i>: Sildenafil and particularly vardenafil were ableto inhibit elimination of cGMP down to 20°C. As the cellular effects of these drugs can cause afterload reduction, they show potential in treating cardiovascular dysfunction during hypothermia. As in normothermia, both drugs showed higher selectivity for inhibition of cGMP-elimination than cAMP-elimination at low core temperatures, indicating that risk for cardiotoxic side effects is not increased by hypothermia.en_US
dc.identifier.citationSelli, Kuzmiszyn, Smaglyukova, Kondratiev, Fuskevåg, Lyså, Ravna, Tveita, Sager, Dietrichs. Treatment of cardiovascular dysfunction with PDE5-inhibitors - temperature dependent effects on transport and metabolism of cAMP and cGMP. Frontiers in Physiology. 2021en_US
dc.identifier.cristinIDFRIDAID 1923771
dc.identifier.doi10.3389/fphys.2021.695779
dc.identifier.issn1664-042X
dc.identifier.urihttps://hdl.handle.net/10037/22622
dc.language.isoengen_US
dc.publisherFrontiers Mediaen_US
dc.relation.journalFrontiers in Physiology
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2021 The Author(s)en_US
dc.subjectVDP::Medical disciplines: 700en_US
dc.subjectVDP::Medisinske Fag: 700en_US
dc.titleTreatment of cardiovascular dysfunction with PDE5-inhibitors - temperature dependent effects on transport and metabolism of cAMP and cGMPen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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