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Bradshaw et al. Vessel Plus 2023;7:35 https://dx.doi.org/10.20517/2574-1209.2023.121 Page 9 of 21

experiments, diazoxide cardioprotection required inhibition of SDH, and the role of K channel activity
ATP
[60]
was not clear . Diazoxide inhibited SDH in the presence of mitoK channel inhibitor 5-
ATP
hydroxydecanoate, and SDH inhibition alone did not lead to an increase in mitochondrial volume (a
surrogate for mitoK activity) . These findings suggested that SDH is not directly upstream of a
[124]
ATP
mitoK channel.
ATP
Reactive oxygen species mimic IPC (attributed to activity at a K channel) and antioxidants block
ATP
IPC [114,115] . The role of ROS was investigated as a potential cardioprotective mechanism of diazoxide .
[67]
Diazoxide and pinacidil increased ROS in cardiomyocytes, and this increase was blocked with the co-
administration of 5-hydrodecanoate or an antioxidant, supporting the hypothesis that ROS are involved in
cardioprotection facilitated by mitoK channels . In isolated perfused rat hearts, ROS generation prior to
[114]
ATP
ischemia onset contributed to the cardioprotection of both IPC and diazoxide . In animal models,
[125]
glutathione (an antioxidant) administered before ischemia prevented cardioprotection by diazoxide, via
prevention of inhibition of SDH or the inhibition of ROS formation . Similarly, a mitochondrial-targeted
[60]
antioxidant that inhibits mitochondrial enzyme complex I MitoSNO (given at reperfusion) reduced
cardioprotection by diazoxide, suggesting an interplay at the mitochondrial level [Figure 1] . Data
[126]
published in 2019 provided further evidence that mitoK is important for redox homeostasis by showing
ATP
that diazoxide results in increased ROS in wild-type mice, but not in cells lacking proposed mitoK
ATP
channel subunits .
[45]
Some have suggested that K cardioprotection and IPC involve the activation of protein kinase C (PKC)
ATP
(specifically PKC-€) and may be blocked by PKC inhibition or genetic deletion [112,127,128] . Diazoxide has also
been implicated in the translocation of PKC-€ from the cytosol to the mitochondria as a mechanism of
[128]
cardioprotection .

Others have evaluated the role of apoptosis in cardioprotection via the exploitation of K channels. In a
ATP
myocyte model, diazoxide and pinacidil protected rat ventricular myocytes against apoptosis . Another
[129]
myocyte study found that diazoxide was protective against apoptosis, although protection depended on the
[130]
timing of treatment . The cardioprotection associated with diazoxide in a swine model was found to result
[131]
from decreased myocyte apoptosis and mitochondrial damage . Recent reviews have also discussed the
inhibition of apoptosis as a potential mechanism of K channel modulation in cardioprotection .
[132]
ATP
TRANSLATIONAL AND HUMAN STUDIES USING K CHANNEL OPENERS FOR
ATP
CARDIOPROTECTION
The studies performed in the 2000s and early 2010s led to knowledge of the basic mechanisms of K
ATP
channels within cells and organelles, providing the framework for understanding how K openers are
ATP
beneficial for cardioprotection, elucidating their mechanisms of action. Over recent years, researchers have
then turned to the potential role of these channels as pharmacologic targets in human patients. To facilitate
the understanding of potassium channel openers at tissue and organism levels, isolated heart models and
intact large animal models that mimic conditions of myocardial ischemia during cardiac surgery have been
developed to test the systemic hemodynamic effects associated with K channel opener diazoxide.
ATP
An early study in 2005 comparing diazoxide to control in a porcine model found that diazoxide did not
provide cardioprotection (infarct size and systolic function) after myocardial ischemia . The authors
[133]
acknowledged that their results were incongruent with others’ findings and postulated that this could be due
to preconditioning effects of anesthetics or an incorrect dose of diazoxide. Recent studies have been more
promising. In an isolated mouse heart model, adding diazoxide to cardioplegia led to improved diastolic