Elucidating the role of K_IR channels in rapid vasodilatation during transition in exercise intensity and different levels of muscle fibre recruitment

Exercise-induced hyperaemia facilitates oxygen delivery to skeletal muscles in accord with their increased metabolic demand. While the link between exercise intensity and local vasodilatation is well established, the underlying mechanisms that trigger and sustain this vasodilatory response remain elusive. One of these key vasodilators which also plays a vital role in muscle activity is the potassium ion (K+). Release of K+ from skeletal muscles during exercise activates inwardly rectifying K+ (KIR) channels and Na+/K+ ATPase found on endothelial and vascular smooth muscle cells (Juel et al. 2007). These changes cause hyperpolarization of smooth muscle cells in arterioles, leading to a reduction of Ca2+ influx and vasodilatation. Hyperaemia during steady-state exercise is known to be partially regulated by activation of KIR channels (Crecelius et al. 2014). However, the contribution of KIR channels to vasodilatory response during transition between exercise intensities is unclear. The KIR channels effect on the differences in vasodilatation observed at constant contractile work but at distinct levels of muscle fibre recruitment also remains elusive. A recent study published in The Journal of Physiology by Terwoord et al. (2020) elucidated two major aspects of the mechanisms contributing to exercise hyperaemia using two protocols in human subjects: the roles of K+ and KIR channels in rapid vasodilatation during transition from mild to moderate intensity exercise, as well as their vasodilatory effect during steady-state exercise with variable degrees of muscle fibre recruitment (Fig. 1). In the first protocol, each participant performed 3 min of mild-intensity handgrip exercise (10% of maximum voluntary contraction) followed by 30 s of moderate intensity contractions (20% of maximum voluntary contraction), repeated in three cycles. Forearm blood flow (FBF) and vascular conductance (FVC, an index of vascular tone) were calculated to determine the degree of vasodilatation. Venous K+ concentration was measured and forearm K+ efflux was calculated to assess changes in these parameters at different workloads. Electromyography (EMG) was also recorded in a subset of participants to evaluate the extent of muscle activation. In order to determine the role of KIR channels on vasodilatation, the subjects were then administered intra-arterial BaCl2, an inhibitor of KIR channels; the protocol and measurements were repeated as in the first run. A time control group of six volunteers were included in the study as well to evaluate any effect of repeated trials on outcome measurements. These participants repeated the trials a second time without the administration of BaCl2. In the second protocol, the authors sought to investigate if KIR channel activation augments vasodilatation independently of exercise intensity. Participants performed two bouts of handgrip exercise with different levels of muscle fibre recruitment while keeping the total contractile force constant (12.5% of maximal voluntary contraction every 4 s, and 25% of maximal voluntary contraction every 8 s). The outcome variables were measured and calculated as in the first protocol, both with and without BaCl2 injection. As expected, vascular blood flow and conductance were higher during moderate intensity compared to mild intensity exercise. Similarly, muscle activation was greater at the moderate workload. However, BaCl2 resulted in a significant reduction of FVC during mild exercise and attenuated the rapid vasodilatation during transition to and throughout moderate intensity exercise substantially. Muscle activation, although increased by BaCl2 administration, was still higher in moderate than mild exercise. These differences were not observed in the time control group who repeated the trials a second time without BaCl2 administration. The findings from the time control group indicate that BaCl2 inhibition of KIR channels, rather than exhaustion or metabolic and physiological changes caused by repeating the exercise trials, was responsible for the attenuation of FVC and increased EMG amplitude. Additionally, venous K+ concentration and forearm K+ efflux were significantly higher both during mild exercise compared to rest, and upon transition from mild to moderate exercise. However, the measurement of these variables after the administration of BaCl2 was hindered by technical difficulties, and thus the authors were unable to confirm the effect of BaCl2 on diminishing venous [K+] and K+ efflux. Nonetheless, these results robustly demonstrate the important role of KIR channels on moderating exercise-induced hyperaemia. The blunting of vasodilatory response by BaCl2 inhibition of KIR channels was assessed as well through KCl infusion which showed 70% reduction in FVC at the highest administered KCl dose. These findings suggest that although KIR channels have a substantial effect on exercise-induced vasodilatation, other mechanisms, such as Na+/K+ ATPase, may also contribute to this response. Alternatively, the dose of intra-arterial BaCl2 used may not have resulted in full inhibition of KIR channels. When comparing low versus high muscle fibre recruitment under constant contractile work, the investigators found significantly higher FVC and muscle activation in the latter. BaCl2 resulted in a significant reduction in FVC in both cases; however, the attenuation of vascular conductance was greater during high fibre recruitment exercise and thus abolished the difference in FVC between the two exercise patterns. Together, the results suggest KIR channels are essential for the augmented vasodilatory response with greater muscle fibre recruitment. Muscle activation was again higher with the infusion of BaCl2, during both low and high muscle fibre recruitment exercise. However, the difference in EMG amplitudes was maintained at similar levels to control trials with significantly higher muscle activation during high versus low fibre recruitment exercise. Partial occlusion of blood flow is previously shown to increase muscle activity (Drouin et al. 2019) which can explain the observed increase in EMG amplitudes during BaCl2 administration. Furthermore, venous [K+] and forearm K+ efflux were higher in both exercise patterns compared to resting values, as expected. Intriguingly, while K+ efflux was greater in high fibre recruitment versus low recruitment, there was no significant difference in venous K+ concentrations. Greater increase in blood flow during high fibre recruitment exercise can lead to dilution and equalization of venous [K+] (Kirby et al. 2013), explaining the similar levels of venous [K+] in the two exercise patterns. While the study by Terwoord et al. has advanced our knowledge regarding the underlying mechanisms involved in exercise-induced vasodilatation, several questions remain elusive. The measurement outcomes of the study are applicable to mild and moderate intensity exercise; future studies should assess the role of KIR channels during strenuous exercise and evaluate its relative contribution to hyperaemia compared to Na+/K+ ATPase and other vasodilatory mechanisms, such as acetylcholine (ACh), nitric oxide and prostaglandins. Also, since BaCl2 administration reduced vasodilatation up to 70%, other factors that contribute to the remaining vasodilatory effect need to be explored. Additionally, KIR channels can be activated through various mechanisms, including K+ released from skeletal muscle cells during exercise, ACh released from endothelial cells, enhanced ATP signalling, stimulation of Ca2+-activated K+ channels, and changes in haemodynamic shear stress (Olesen et al. 1988). More research is needed to untangle these factors that affect the activation of KIR channels. Furthermore, technical difficulties and limitations with equipment availability prevented the investigators from confirming some of their findings by measuring venous K+ concentration and K+ efflux after the administration of BaCl2. Although BaCl2 inhibition of KIR channels is still the most likely explanation of the observed changes in vasodilatory response, other electrochemical modulations caused by infusion of BaCl2 cannot be excluded. Measurement of [K+] after BaCl2 infusion can also provide insight into the greater muscle activation, as observed by higher EMG amplitudes, with BaCl2. The lack of a difference in venous [K+] between low and high muscle fibre recruitment exercises was attributed to potential dilution caused by parallel increase in blood flow in the latter; measurement of interstitial [K+] in future studies can elucidate whether extracellular K+ levels vary based on the extent of fibre recruitment. Further investigation is also needed to determine if the immediate vasodilatory effect of muscle contractions is primarily facilitated by KIR channels on endothelial or vascular smooth muscle cells. The rapid vasodilatation in response to transition to higher intensity exercise is shown to be facilitated by KIR channels as inhibition of these channels results in abolition of the vasodilatory response. In addition, higher muscle fibre recruitment, independent of exercise intensity, increases hyperaemia and KIR channels appear to be a major contributor to this physiological response. The K+ released from contracting muscle fibres can activate KIR channels on endothelial and vascular smooth muscle cells in a feed-forward process, causing vascular hyperpolarization and vasodilatation. Terwoord et al. (2020) provide a solid foundation to examine the underlying mechanisms involved in exercise-induced hyperaemia. Their work can be expanded in the future to unravel other factors that stimulate KIR channels as well as other mediators of vasodilatation at various exercise intensities. None. Both authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None.

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