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

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 (K-IR) 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 (231 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), K-IR channel inhibition (BaCl2), combined inhibition of K-IR channels and Na+/K+-ATPase (BaCl2 and ouabain, respectively), and combined inhibition of K-IR channels, Na+/K+-ATPase, NO, and prostaglandins (BaCl2, ouabain, l-NMMA [N-G-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%; P<0.05), whereas ouabain and l-NMMA plus ketorolac did not. Total FBF (area under the curve) was attenuated by BaCl2 (-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 K-IR channels is the primary determinant of peak RH, whereas activation of both K-IR channels and Na+/K+-ATPase explains nearly all of the total (AUC) RH in humans.