Electrical amplification: K_IR channels taking centre stage in the hyperaemic debate

Arterial networks in skeletal muscle or other key organs are composed of thousands of segments whose principal role is to match perfusion with energetic demand. Functional hyperaemia is typically rationalized as a two-step process that begins with parenchymal cells producing stimuli, which then diffuse to the arterial wall, driving dilatation and graded tone relaxation. Stimulus identity is an issue that has consistently captured the imagination of biologists, with candidate molecules characteristically tied to metabolism, haemodynamic forces and oxygen content. How stimuli precisely induce network dilatation has received markedly less attention, an issue particularly acute in humans. In considering functional hyperaemia, it is important to recognize that blood flow resistance is a broadly distributed parameter, and thus marked changes in perfusion only occur when arterial segments, and the thousands of cells within, respond as a coordinated unit. Coordinated responses depend, at a foundational level, on the sharing of a common signal among interconnected vascular cells. Ions are that common signal, entering and exiting vascular tissue through gated ion channels; the charge they carry is then distributed among constitutive members via gap junctions (Welsh et al. 2018). The ensuing VM response drives changes in cytosolic [Ca2+], myosin light chain kinase activity and finally myosin phosphorylation across the vessel. Multiple K+ channels have been intimately tied to initiating hyperpolarization and dilatation, each presumably activated by defined stimuli and working independently of one another. Vascular inward rectifying K+ (KIR) channels, albeit expressed on the plasma membrane of smooth muscle and/or the endothelial cells, are composed of four α-subunits from the KIR2.x subfamily. While viewed as an unexciting background conductance, KIR channels retain one regulatory property often thought of as important to functional hyperaemia. That property centres on the release of K+ from active tissue, elevating the extracellular concentration, a change that would enhance KIR channel activity through the loosening of a voltage-dependent Mg2+/polyamine block. Notably absent from such discussions is acknowledgment of negative slope conductance, a property which paradoxically ensures a rise in KIR activity with hyperpolarization, in stark contrast to other vascular K+ conductances (Welsh et al. 2018). This intrinsic property allows KIR channels to be defined as ‘electrical amplifiers’, integral membrane proteins facilitating the hyperpolarization and robust dilatation initiated by other K+ conductances (Jantzi et al. 2006; Smith et al. 2008; Sonkusare et al. 2016). It is the concept of ‘electrical amplification’ as first recognized in rodent models, that, in an article in this issue of The Journal of Physiology, Hearon and colleagues (2019) have translated to humans, gaining insight into the hyperaemic response of skeletal muscle. Their approach was simple and carefully crafted: measure forearm blood flow and calculate vascular conductance in response to infused agents during handgrip exercise while introducing BaCl2 to selectively block KIR channels. In keeping with the idea of electrical amplification, exercise amplified the vasodilatory response to acetylcholine, a hyperpolarizing stimulus, but had no measureable effect on hyperaemia induced by sodium nitropusside, an agent that relaxes smooth muscle independent of membrane potential. Arterial BaCl2 infusion attenuated the hyperaemic responses to handgrip exercise and abolished the amplification of acetylcholine, perturbations that activate KATP and small/intermediate conductance Ca2+-activated K+ channels. Equally important to this study was a judicious set of controls that noted functional expression of KIR channels in forearm vasculature capable of amplifying acetylcholine-mediated vasodilatation. What makes this study particularly notable is how it persuades vascular biologists to recognize ion channel cooperativity, with robust electrical responses best achieved by working together. Thus, there is no single channel responsible for functional hyperaemia; some will initiate the response while others ‘amplify’ the response given their intrinsic biophysical properties. Looking forward, it is intriguing to consider the translational value of ongoing rodent work highlighting how lifestyle (i.e. stress) and cardiovascular (i.e. dyslipidaemia) risk factors diminish KIR channel activity. Such diminishment in humans would predictably lead to permissive vascular dysfunction, blunting any and all hyperaemic responses tied to vascular K+ channel activation. Food for thought and room for further translational development. None declared. Sole author. This article was supported by operational support from the Natural Science and Engineering Research Council of Canada. The author is the Rorabeck Chair in Molecular Neuroscience and Vascular Biology.

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