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Page 14 of 21 Bradshaw et al. Vessel Plus 2023;7:35 https://dx.doi.org/10.20517/2574-1209.2023.121

Figure 5. Mechanistic depiction of neuron mitochondria with ketamine, glutamate, diazoxide, and other second messengers and
potential mechanisms of injury during hypothermic circulatory arrest. This picture depicts a neuron with intracellular,
intramitochondrial, and nuclear potential mechanisms of injury during hypothermic circulatory arrest. Both ketamine and diazoxide
have potential neuroprotective effects. Ketamine is depicted here as affecting the NMDA receptors and subsequent second
messengers within cytosol. Diazoxide is depicted as acting on the mitochondrial membrane at the mitoK ATP channel and Complex II.
Both pathways eventually affect ROS within the mitochondria. Downstream effects of both pathways are also thought to involve
mechanisms within the nucleus that lead to DNA changes and apoptosis. Exploration of positive synergism of these agents is one
option for future directions in neuroprotection research [149] . This figure was created by Mary Ann Wilson, PhD, and is used with her
permission. A version of this figure was also previously published [149] . This figure is used with permission from Elsevier (obtained
December 7, 2023, license number 5683710387270). ROS: Reactive oxygen species; MitoK : mitochondrial K channel; AMPA:
ATP ATP
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA: N-methyl-D-aspartate; Cyt C: cytochrome C; DNA: deoxyribonucleic
acid; NO: nitric oxide free radical.

cardioprotection in cardiac surgery patients has been demonstrated as safe and feasible [137,138] , more data are
needed in high-risk human patients and with the use of hypothermic, hyperkalemic blood cardioplegia.

Important fundamental questions remain about K channels. One unanswered question was made
ATP
apparent in a recent study in which diazoxide was combined with a mitochondria-targeted S-nitrosating
agent (mitoSNO). Each of these agents was known to be cardioprotective individually. However, the
cardioprotective mechanism of diazoxide was found to be exclusive of the mechanism of MitoSNO; when
[126]
combined, these agents were not beneficial . The authors concluded that using nitric oxide donators could
be detrimental in the presence of diazoxide, and this requires further investigation. The idea of exploring
the positive and negative synergism of diazoxide with various other pharmacological agents should be
further studied in both cardioprotection and neuroprotection. It will be critical to know which agents might
enhance or negate the beneficial effects of diazoxide or other K agents.
ATP