Amplification of Endothelium‐Dependent Vasodilatory Signaling in Contracting Skeletal Muscle of Humans: Role of Inwardly Rectifying Potassium Channels

The local vasodilatory response to muscle contraction is due in part to the activation of inwardly rectifying potassium (K IR ) channels and subsequent smooth muscle cell hyperpolarization. In addition to direct activation of K IR channels via elevated extracellular potassium, K IR channels may function as “amplifiers” of electrical signals originating from the endothelium and thus augment vasodilatory responsiveness to endothelium‐derived hyperpolarizing signals. In this study, we tested the hypothesis that exercise will selectively amplify vasomotor responses to the endothelium‐dependent vasodilator acetylcholine (ACh) and that this effect will be mediated in part by activation of K IR channels. Methods In a total of 15 young adults, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to local intra‐arterial infusion of ACh or sodium nitroprusside (SNP) during: 1) control resting conditions, 2) mild handgrip exercise (5% maximum voluntary contraction [MVC]), or 3) pharmacologically induced vasodilation (either by ACh or SNP infusion) to match the level of hyperemia observed during mild exercise, thus serving as a “high flow” resting condition. In the case of ACh, similar trials were performed before and after blockade of K IR channels via infusion of barium chloride, or pharmacological activation of K IR channels via infusion of potassium chloride (KCl). Results Mild handgrip exercise significantly augmented the peak vasodilatory response to the endothelium‐dependent vasodilator ACh (Δ FVC: control: 116 ± 13; exercise: 253 ± 19 ml/min/100mmHg; P<0.01; +124 ± 12%) but not the endothelium‐independent vasodilator SNP (Δ FVC: control: 144 ± 33; exercise: 116 ± 21ml/min/100mmHg; P=NS). There was no effect of high flow per se on peak vasodilatory response to ACh or SNP (Δ FVC: ACh: 143 ± 18; SNP: 125 ± 37 ml/min/100mmHg; both P=NS vs. respective control). Blockade of K IR channels attenuated the exercise‐induced augmentation of ACh‐mediated dilation (Δ FVC: control: 189 ± 24; exercise: 198 ± 19 ml/min/100mmHg; +9 ± 12%). In a follow up study, direct pharmacological activation of K IR channels via infusion of KCl amplified peak ACh‐mediated vasodilation relative to control ACh infusion (Δ FVC: control: 97 ± 15 vs. 142 ± 16 ml/min/100mmHg; respectively; +50± 9%). These findings provide evidence that muscle contractions amplify endothelium‐dependent vasodilatory signaling via activation of K IR channels in humans. Further, these studies support the idea that K IR channels may act as “amplifiers” of endothelium‐dependent hyperpolarization and that this may be an important mechanism contributing to the normal vasodilatory response to exercise. Support or Funding Information HL119337, HL095573