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Page 10 of 21 Bradshaw et al. Vessel Plus 2023;7:35 https://dx.doi.org/10.20517/2574-1209.2023.121

Figure 1. Electron transport chain with K ATP channel and actions of MitoSNO and diazoxide. The schema simplifies the activity of the
inner membrane of the mitochondrion, including the proposed K ATP channel and electron transport chain. At the bottom of the figure, a
photo taken by electron microscopy from the Lawton laboratory, of individual mitochondria. In the schema, diazoxide is depicted as
having an inhibitory effect on Complex II (succinate dehydrogenase) while activating the K ATP channel. The cardioprotection by
diazoxide may occur due to either of the mechanisms or another mechanism. MitoSNO has an inhibitory effect on Complex I, which
prevents SDH accumulation, and this is thought to be the cardioprotective mechanism of MitoSNO. While each is cardioprotective via
these mechanisms, these two agents have a synergistic negative effect [126] . This figure is used with permission from Elsevier (obtained
September 4, 2023, license number 5621920353581) [126] . MitoSNO: Mitochondria-targeted S-nitrosating agent; NADH: nicotinamide
adenine dinucleotide, reduced form; NADþ: nicotinamide adenine dinucleotide, oxidized form; ROS: reactive oxygen species; ATP:
adenosine triphosphate; ADP: adenosine diphosphate; Cyt C: cytochrome C.

[134]
function following a period of global ischemia .Two subsequent studies were conducted in swine models.
In the first, swine treated with hypothermic, hyperkalemic cardioplegia with diazoxide (single dose) prior to
a 2-h global ischemic period were found to have improved systolic and diastolic ventricular function
compared to cardioplegia alone [Figure 2] . In the second, swine underwent 30 min of occlusion of the
[135]
left anterior descending artery prior to 2 h of global ischemia protected with cardioplegia or cardioplegia
[136]
with diazoxide (dosed every 20 min) [Figure 3] . Compared to cardioplegia alone, animals that received
diazoxide had decreased myocardial stunning and shortened time to separate from cardiopulmonary bypass
[Figure 4] . These studies provided some of the most convincing preclinical data to date that diazoxide
[136]
will be beneficial as an additive to cardioplegia in humans undergoing cardiac surgery requiring global
ischemia. It is important to acknowledge the limitations of the translational models that have been widely
used to study K channels and cardioprotection. These models may not provide sufficient confidence to
ATP
translate to human pathophysiology. These limitations highlight the importance of randomized clinical
trials in humans before widespread adoption.

Two small, randomized trials in humans have investigated the cardioprotective effects of diazoxide in
humans [137,138] . Wang et al. (2003) randomized 40 patients undergoing coronary artery bypass grafting to
receive either 1.5 mg/kg diazoxide infusion or placebo intravenously prior to undergoing global ischemia for
cardiac surgery. They found improved hemodynamic recovery after surgery in patients who received
diazoxide, though they noted that further studies were needed to determine an optimal dosing protocol .
[137]
Deja et al. (2009) randomized 40 patients to receive intermittent warm blood cardioplegia that was
[138]
supplemented with 100 µmol/L diazoxide or placebo prior to global ischemia for cardiac surgery . They
found that patients treated with diazoxide required less inotropic support and had higher cardiac indices
[138]
after global ischemia . Both human studies were small, involved low-risk patients, and were primarily