Cardioprotective mechanisms of mitochondria-targeted S-nitrosating agent and adenosine triphosphate-sensitive potassium channel opener are mutually exclusive
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Authors
Ahmad, T
Wang, J
Velez, AK
Suarez-Pierre, A
Clement, KC
Dong, J
Sebestyen, K
Canner, JK
Murphy, MP
Lawton, JS
Publication Date
2021-12-18Journal Title
The Journal of Thoracic and Cardiovascular Surgery
ISSN
0022-5223
Publisher
Elsevier
Volume
8
Pages
338-354
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Ahmad, T., Wang, J., Velez, A., Suarez-Pierre, A., Clement, K., Dong, J., Sebestyen, K., et al. (2021). Cardioprotective mechanisms of mitochondria-targeted S-nitrosating agent and adenosine triphosphate-sensitive potassium channel opener are mutually exclusive. The Journal of Thoracic and Cardiovascular Surgery, 8 338-354. https://doi.org/10.1016/j.xjon.2021.07.036
Abstract
Background: 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.
Sponsorship
MRC (MC_UU_00015/3)
Wellcome Trust (220257/Z/20/Z)
Identifiers
External DOI: https://doi.org/10.1016/j.xjon.2021.07.036
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336350
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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