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Page 2 of 21 Bradshaw et al. Vessel Plus 2023;7:35 https://dx.doi.org/10.20517/2574-1209.2023.121

Pathology associated with K channels can result from decreased or increased function, depending on the
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specific mutation and subunit affected. Loss of function of K channels results in hyperinsulinism and
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vascular hypercontractility [16,17] , whereas gain of function leads to prolonged PR intervals, arrhythmias, and
hypotension [2,3,18-20] . The pathology of Cantu syndrome (hypertrichosis-osteochondrodysplasia-cardiomegaly
syndrome) results from genetic gain of function of K channel subunits, resulting in abnormalities
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including cardiac enlargement and ventricular hypertrophy, pericardial effusion, pulmonary hypertension,
and hypertrichosis [11,21] . Understanding the abnormalities in Cantu syndrome is informative with regard to
the non-pathologic role of K channels in human physiology . Some pharmacologic agents that activate
[22]
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K channels may cause some of the same changes as those seen in Cantu syndrome, and this modulation
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of these channels has the potential to be beneficial [11,23,24] .
The body of literature on the nature and role of K channels in various tissues has grown steadily over
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recent decades. A subset of literature focuses on the role of these channels in cardiac disease . Activation of
[25]
K channels is involved in cardioprotection or preservation of the myocardium during stress, such as the
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[26]
global ischemia imposed during cardiac surgery . The channels are similarly involved in the protection of
the neural cortex and spinal cord [27-29] . Previous authors have reviewed the early basic science of K
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channels [30-33] . In this review, we highlight recent evidence with a focus on the role of these channels in
cardioprotection and neuroprotection during cardiac surgery.

STRUCTURE AND FUNCTION OF K CHANNELS
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Cardiac myocytes contain two K channel entities: one located in the sarcolemmal membrane (sK ) and
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a proposed mitochondrial channel (mitoK ). The structure and function of sK and mitoK appear to
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be related but with important differences [34-36] . The well-characterized sK channel has been cloned and is
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present at a very high density in the heart (2,000-3,000/myocyte) . The sK channel is a hetero-octamer
[37]
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+
of four pore-forming polypeptides of the inwardly rectifying K channel family Kir6.x and four sulfonylurea
receptor subunits of the superfamily of ATP-binding cassette transporters [38-40] . The sulfonylurea receptor
(SUR) subunit represents the site for blockade by sulfonylureas and stimulation by potassium channel
openers and adenosine diphosphate (ADP). The Kir6.x subunit is the location for inhibition by ATP [38,40] .
The mitoK channel may be primarily responsible for the cardioprotection provided by K channel
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ATP
modulation [26,41] , but the sK channel is better characterized and may also be involved . The physiological
[42]
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role of the sK channel in cardiac tissue involves modulating cellular function in response to stress such as
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metabolic inhibition [25,43] . Specifically, the channel is opened in response to stress and closed (inhibited) in
the presence of ATP . The function of the mitoK channel appears to involve organelle response to
[44]
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stress, with effects on both the volume and the function of the mitochondria [45-47] .
The focus of this review is the role function of K channels in the myocardium. However, K channels
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are present in cardiac muscle, skeletal muscle, and smooth muscle, and their function in smooth muscle is
worth noting in this discussion about the cardiovascular effects of K channels . Diazoxide is a K
[48]
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channel opener that has been found to cause substantial arterial and arteriolar dilatation [49,50] . This agent was
first used clinically as an antihypertensive agent before its potential as a cardioprotective agent was
[51]
identified . The side effects of diazoxide have limited its clinical use for hypertension, though it is still used
clinically primarily to treat hypoglycemia [52-55] . The role of K channels in causing hypotension is primarily
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attributed to the vascular smooth muscle cells ; however, these channels are also found in vascular
[2,3]
endothelial cells, and the action in endothelial cells may contribute to the effects on vascular tone [56,57] .