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Page 4 of 21 Bradshaw et al. Vessel Plus 2023;7:35 https://dx.doi.org/10.20517/2574-1209.2023.121

The use of carefully designed cardioplegia solutions to facilitate cardiac arrest during surgery has been the
primary method of protection from global ischemia, but the cardioplegia itself contributes to myocyte
[82]
injury . The use of K channel openers may offer protection against such injury. Advancements in
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understanding how myocardial K channels are involved in cardioprotection have occurred over the last
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several decades. [Table 1] This research has progressed towards safely using K channel openers for the
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benefit of human patients with cardiac disease, though they are not yet used clinically for this purpose.
In 1983, Noma demonstrated that the K channel was involved in the regulation of energy metabolism in
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[1]
cardiac cells . For the past 40 years since Noma’s study was published, there have been ongoing efforts to
understand and utilize K channels for patients with cardiac pathology. Murry et al. published data
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demonstrating non-pharmacologic cardioprotection with IPC in dogs, which was a catalyst for subsequent
[83]
work exploring the mechanism of IPC . In 1992, Gross et al. demonstrated that the benefits of
preconditioning in dogs were abolished by blocking the K channel pharmacologically [84,85] . The link
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between cardioprotection and K channels was then established, and led to further studies seeking to
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exploit the K channel for pharmacologic cardioprotection .
[86]
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In the mid- to late-1990s, many experiments were performed on isolated animal hearts in a Langendorff
apparatus model to further explore the potential of pharmacologic cardioprotection with different K
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channel openers. The Langendorff perfused heart model refers to a procedure that is useful for experiments
in which the goal is to evaluate heart function in response to medications or ischemia-reperfusion. The
method involves using an isolated heart perfused via the aorta and, thus, the coronary arteries [87-89] . Such
models can utilize physiologic crystalloid perfusion or blood perfusion to more closely mimic clinical
situations . Pinacidil and aprikalim are two K channel openers that were used in early studies to assess
[90]
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cardioprotection, and both were found to be protective during cardiac ischemia. The benefit of pinacidil
was compared to St. Thomas’ solution (a commonly used hyperkalemic cardioplegia solution ); Pinacidil
[91]
provided better postischemic recovery in isolated hearts after ischemia [90,92,93] . K channel openers were
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found to be effective in crystalloid hypothermic, hyperkalemic cardioplegic solutions, in blood cardioplegia,
and in the acutely injured heart [90,93,94] . The cardioprotective effect of pinacidil when added to hypothermic
depolarizing cardioplegia was lost with a K blocker, suggesting that the benefit involved K channels .
[94]
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Multiple K channel openers have been studied for cardioprotection, and each has a different
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pharmacology. Pinacidil was used in many early studies evaluating K channel openers and
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cardioprotection, but many researchers have since focused on diazoxide due to its proposed specificity for
mitoK channels, unlike most other K channel openers . Garlid found that diazoxide has a 2,000-fold
[34]
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greater affinity for mitoK compared to the sarcolemmal K channel . However, some of the other
[95]
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potassium channel openers including cromakalim, nicorandil, and pinacidil may still have some role in
some role in cardioprotection . Comparisons of cromakalim and diazoxide suggested that diazoxide has
[96]
[97]
less effect on cardiac action potential duration than some other potassium channel openers . The
shortening of the cardiac action potential has been proposed as a mechanism of cardioprotection by K
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channel openers .
[98]
THE MOLECULAR MECHANISM OF CARDIOPROTECTION AFFORDED BY K CHANNEL
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ACTIVATION IS UNKNOWN
The understanding of K channels on mitochondrial membranes developed in the 1990s after they were
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characterized by Inoue et al. in 1991 . The interest in the mitoK channel for cardioprotection was
[99]
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proposed to be based on responses of mitochondria to stress. As previously stated, mitoK channels open
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during stress, which facilitates increased mitochondrial volume and reduced calcium overload, both of
which are beneficial for mitochondrial function and overall cellular adaptation [45,100] .