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dc.contributor.authorAhmad, T
dc.contributor.authorWang, J
dc.contributor.authorVelez, AK
dc.contributor.authorSuarez-Pierre, A
dc.contributor.authorClement, KC
dc.contributor.authorDong, J
dc.contributor.authorSebestyen, K
dc.contributor.authorCanner, JK
dc.contributor.authorMurphy, MP
dc.contributor.authorLawton, JS
dc.date.accessioned2022-04-21T23:30:46Z
dc.date.available2022-04-21T23:30:46Z
dc.date.issued2021-12-18
dc.identifier.issn0022-5223
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/336350
dc.description.abstractBackground: Myocytes exposed to stress exhibit significant swelling and reduced contractility. These consequences are ameliorated by adenosine triphosphate–sensitive potassium (KATP) channel opener diazoxide (DZX) via an unknown mechanism. KATP channel openers also provide cardioprotection in multiple animal models. Nitric oxide donors are similarly cardioprotective, and their combination with KATP activation may provide synergistic benefit. We hypothesized that mitochondria-targeted S-nitrosating agent (MitoSNO) would provide synergistic cardioprotection with DZX. Methods: Myocyte volume and contractility were compared following Tyrode's physiologic solution (20 minutes) and stress (hyperkalemic cardioplegia [CPG] ± DZX; n = 5-20 each; 20 minutes) with or without MitoSNO (n = 5-11 each) at the end of stress, followed by Tyrode's solution (20 minutes). Isolated mouse hearts received CPG ± DZX (n = 8-10 each) before global ischemia (90 minutes) with or without MitoSNO (n = 8 each) at the end of ischemia, followed by reperfusion (30 minutes). Left ventricular (LV) pressures were compared using a linear mixed model to assess the impact of treatment on the outcome, adjusting for baseline and balloon volume. Results: Stress (CPG) was associated with reduced myocyte contractility that was prevented by DZX and MitoSNO individually; however, their combination was associated with loss of cardioprotection. Similarly, DZX and MitoSNO improved LV function after prolonged ischemia compared with CPG alone, and cardioprotection was lost with their combination. Conclusions: MitoSNO and DZX provide cardioprotection that is lost with their combination, suggesting mutually exclusive mechanisms of action. The lack of a synergistic beneficial effect informs the current knowledge of the cardioprotective mechanisms of DZX and will aid planning of future clinical trials.
dc.publisherElsevier
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titleCardioprotective mechanisms of mitochondria-targeted S-nitrosating agent and adenosine triphosphate-sensitive potassium channel opener are mutually exclusive
dc.typeArticle
dc.publisher.departmentDepartment of Medicine
dc.date.updated2022-04-21T10:32:05Z
prism.endingPage354
prism.publicationDate2021
prism.publicationNameThe Journal of Thoracic and Cardiovascular Surgery
prism.startingPage338
prism.volume8
dc.identifier.doi10.17863/CAM.83770
dcterms.dateAccepted2021-07-30
rioxxterms.versionofrecord10.1016/j.xjon.2021.07.036
rioxxterms.versionVoR
dc.contributor.orcidMurphy, Mike [0000-0003-1115-9618]
dc.identifier.eissn2666-2736
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMRC (MC_UU_00015/3)
pubs.funder-project-idWellcome Trust (220257/Z/20/Z)
cam.issuedOnline2021-08-08
cam.depositDate2022-04-21
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial-NoDerivatives 4.0 International