Reactive Hyperemia Occurs via Activation of Inwardly-Rectifying Potassium Channels and Na+/K+-ATPase in Humans

Anne R. Crecelius, University of Dayton
Jennifer C. Richards, Colorado State University - Fort Collins
Gary J. Luckasen, Medical Center of the Rockies Foundation
Dennis G. Larson, Medical Center of the Rockies Foundation
Frank A. Dinenno, Colorado State University - Fort Collins

This is the peer-reviewed version of the following article:

Crecelius A.R., J.C. Richards, G.J. Luckasen, D.G. Larson and F.A. Dinenno. Reactive hyperemia occurs via activation of inwardly-rectifying potassium channels and Na+/K+-ATPase in humans. Circ Res. 113(8):1023-32. 2013.

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Rationale: Reactive hyperemia (RH) in the forearm circulation is an important marker of cardiovascular health, yet the underlying vasodilator signaling pathways are controversial and thus remain unclear.

Objective: We hypothesized that RH occurs via activation of inwardly rectifying potassium (KIR) channels and Na+/K+-ATPase and is largely independent of the combined production of the endothelial autocoids nitric oxide (NO) and prostaglandins in young healthy humans.

Methods and Results: In 24 (23±1 years) subjects, we performed RH trials by measuring forearm blood flow (FBF; venous occlusion plethysmography) after 5 minutes of arterial occlusion. In protocol 1, we studied 2 groups of 8 subjects and assessed RH in the following conditions. For group 1, we studied control (saline), KIR channel inhibition (BaCl2), combined inhibition of KIR channels and Na+/K+-ATPase (BaCl2 and ouabain, respectively), and combined inhibition of KIR channels, Na+/K+-ATPase, NO, and prostaglandins (BaCl2, ouabain, L-NMMA [NG-monomethyl-L-arginine] and ketorolac, respectively). Group 2 received ouabain rather than BaCl2 in the second trial. In protocol 2 (n=8), the following 3 RH trials were performed: control; L-NMMA plus ketorolac; and L-NMMA plus ketorolac plus BaCl2 plus ouabain. All infusions were intra-arterial (brachial). Compared with control, BaCl2 significantly reduced peak FBF (−50±6%; P2 (−61±3%) and ouabain (−44±12%) alone, and this effect was enhanced when combined (−87±4%), nearly abolishing RH. L-NMMA plus ketorolac did not impact total RH FBF before or after administration of BaCl2 plus ouabain.

Conclusions: Activation of KIR channels is the primary determinant of peak RH, whereas activation of both KIR channels and Na+/K+-ATPase explains nearly all of the total (AUC) RH in humans.