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Bradshaw et al. Vessel Plus 2023;7:35 https://dx.doi.org/10.20517/2574-1209.2023.121 Page 13 of 21

Table 2. Published research demonstrating or relating to the importance of the K ATP channel in neuroprotection

Reference (author, year) Model Findings

[145]
Garcia de Arriba et al., 1999 Rat neocortical tissue ATP-dependent potassium channels were neuroprotective during hypoxia in rat neocortical tissues
[146]
Domoki et al., 1999 Swine model Diazoxide preserved neuronal-vascular function after cerebral ischemia in newborn pigs
[144]
Debska et al., 2001 Rat hippocampal tissue Potassium channel openers depolarized hippocampal mitochondria
[28]
Shake et al., 2001 Canine model Intravenous diazoxide was neuroprotective in dogs undergoing cardiopulmonary bypass
[29]
Caparrelli et al., 2002 Rabbit model Diazoxide pretreatment resulted in improved neurologic outcomes, and the mechanism appeared to be due to the K ATP channel activity
[148]
Teshima et al., 2003 Cerebellar neurons MitoK ATP channel openers inhibited apoptosis by preserving mitochondrial inner membrane potential
[147]
Barreiro et al., 2006 Canine model Pretreatment with diazoxide plus HCA led to improved neurologic outcomes versus HCA alone
[151]
Yamanaka et al., 2018 Mouse model Diazoxide and EPO were synergistically protective of the spinal cord after ischemia with upregulation of a common receptor
[152]
Yamanaka et al., 2019 Mouse model Diazoxide and EPO were synergistically protective of the spinal cord after ischemia via upregulation of NGF
[150]
Yamanaka et al., 2019 Mouse model Oral diazoxide preserved motor function in spinal cord ischemia-reperfusion injury by the STAT3 pathway
[153]
Ikeno et al., 2023 Mouse model Direct and indirect activation of mitoK channels were involved pharmacological spinal cord protection with motor function preservation
ATP
EPO: Erythropoietin; NGF: nerve growth factor; STAT3: signal transducer and activator of transcription; HCA: hypothermic circulatory arrest.

The mechanism of diazoxide for neuroprotection is similar to one of many proposed for its cardioprotective action. Diazoxide is a K channel opener that
ATP
inhibits complex II and maintains mitochondrial membrane potential. This prevents mitochondrial dysfunction and cell death following DHCA and injury
due to N-methyl-D-aspartate (NMDA) excitotoxicity via unique pathways and could be utilized to produce synergistic benefit with NMDA blockade during
cardiac surgery with DHCA [Figure 5] .
[149]

Early studies on neuroprotection focused on the brain cortex, but more contemporary work evaluated K channels and protection of the spinal cord, which is
ATP
applicable to cardiac surgical procedures on the descending aorta that have a known complication of paraplegia from spinal ischemia. Diazoxide attenuated
spinal cord ischemia-reperfusion injury, and motor function after spinal cord ischemia was improved in a mouse model with diazoxide compared to controls,
an action that appeared to be associated with expression of the signaling transducer and activator of transcription (STAT) 3 pathway . These results have
[150]
been confirmed by several others that have demonstrated the potential of diazoxide to reduce spinal cord injury following ischemia [151-153] .

Further work is needed to characterize the mechanisms involved in neuroprotection provided by diazoxide and its potential use in cardiac surgery.

FUTURE DIRECTIONS

Future work will further advance the understanding of the function and potential of K channels for the benefit of patients undergoing cardiac surgery.
ATP
Perhaps one of the most anticipated future endeavors is a large clinical trial using diazoxide as an additive to cardioplegia. While the use of diazoxide for