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 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 (PGs) 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) following 5 minutes of arterial occlusion. In Protocol 1, we studied 2 groups of 8 subjects and assessed RH in the following conditions; Group 1:control (saline), KIR channel inhibition (barium chloride; BaCl2), combined inhibition of KIR channels and Na+/K+-ATPase (BaCl2+ouabain, respectively), and combined inhibition of KIR channels, Na+/K+-ATPase, NO and PGs (BaCl2+ouabain+L-NMMA+ketorolac, respectively). Group 2 received ouabain rather than BaCl2in the 2nd trial. In Protocol 2 (n=8), 3 RH trials were performed: control, L-NMMA+ketorolac, and L-NMMA+ketorolac+BaCl2+ouabain. All infusions were intra-arterial (brachial). Compared to control, BaCl2 significantly reduced peak FBF (-50±6%; P<0.05) whereas ouabain and L-NMMA+ketorolac did not. Total FBF (area under 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+ketorolac did not impact total RH FBF prior to or after administration of BaCl2+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 total RH in humans.
- Received May 6, 2013.
- Revision received August 6, 2013.
- Accepted August 12, 2013.