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Bradshaw et al. Vessel Plus 2023;7:35 https://dx.doi.org/10.20517/2574-1209.2023.121 Page 7 of 21

Makepeace et al., Mouse heart, Langendorff Adding diazoxide to cardioplegia provided improved recovery after ischemia
[134]
2018
[45]
Paggio et al., 2019 HeLa cells with plasmids encoding K proteins and Over- or under-expression of mitoK is detrimental. Cardioprotection by diazoxide is lost when mitoK is suppressed
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mouse models
Suarez-Pierre et al., Swine model Diazoxide preserved systolic and diastolic ventricular function after ischemia in a large animal model
[135]
2020
[126]
Ahmad et al., 2021 Mouse myocytes S-nitrosating agent and diazoxide are cardioprotective individually, but the beneficial effect was lost when they were combined
[136]
Velez et al., 2022 Swine model Diazoxide reduced myocardial stunning and facilitated separation from cardiopulmonary bypass
[59]
Wang et al., 2023 Mouse myocytes and hearts Neither Kir1.1 (ROMK) nor SUR1 were involved in the mechanism of cardioprotection by diazoxide

K : Adenosine triphosphate-sensitive potassium channels; mitoK : mitochondrial adenosine triphosphate-sensitive potassium channels; IPC: ischemic preconditioning; 5-HD: 5-hydroxydecanoate; SDH:
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succinate dehydrogenase; SUR1: sulfonylurea sensitive regulatory subunit 1; STAT3: signal transducer and activator of transcription 3; SUR 1: sulfonylurea sensitive regulatory subunit 1; ROMK: renal outer medullary
potassium.

Diazoxide and perhaps other K channel openers were initially suggested to be cardioprotective via a mechanism involving a mitoK channel rather than a s
ATP
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K channel in the few years after the mitoK channels were characterized [26,33] . Efforts to define the role of both sarcolemmal and mitochondrial channels
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involved in cardioprotection were begun. Pharmacologic cardioprotection and non-pharmacologic cardioprotection using IPC were compared: both were
cardioprotective, and the cardioprotection initially appeared to be inhibited in the presence of a selective mitoK channel blocker, 5-hydroxydecanoate .
[101]
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Additionally, when a mitoK channel blocker was added to isolated hearts with either diazoxide or IPC, this abolished the improvement in contractility after
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ischemia that had been afforded by diazoxide but not by IPC, suggesting that a mitoK was critical for diazoxide’s mechanism but not for IPC . In line with
[86]
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these findings, a later study using genetic deletion found that diazoxide’s cardioprotection was not due to action at a sK channel .
[41]
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Ultimately, the molecular mechanism of action at a proposed mitoK channel remains unknown. Potential mechanisms largely focus on the mitochondria
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and include K channel-related and non-related mechanisms . It is also possible that the effects of diazoxide and other K channel openers can be
[42]
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attributed to a combination of mechanisms .
[102]
POTENTIAL MECHANISMS OF CARDIOPROTECTION (K CHANNEL AND CHANNEL-INDEPENDENT)
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Mitochondrial and cellular volume alteration
Both cellular and mitochondrial volume alterations have been investigated in the search for mechanisms of cardioprotection relating to K channels and their
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[30]
+
openers. While opening sK channels results in K efflux from the cell , opening of a mitoK channel results in K influx from the cytosol into the
+
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mitochondria and mitochondrial swelling, suggesting a potential basis for mitoK -dependent changes in mitochondrial and cellular volume alteration during
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to stress [32,46,67] . Interestingly, opening the mitoK channel was associated with changes in mitochondrial matrix volume, calcium concentration, and
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