Reactive hyperemia occurs via activation of inwardly rectifying potassium channels and Na+/K+-ATPase in humans.
BACKGROUND
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.


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 [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 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.
From the Human Cardiovascular Physiology Laboratory, Department of Health and Exercise Science, and Vascular Physiology Research Group, Department of Biomedical Sciences, Colorado State University, Fort Collins, CO; and Medical Center of the Rockies Foundation, University of Colorado Health, Loveland, CO.
Anne R
AR
Crecelius
Jennifer C
JC
Richards
Gary J
GJ
Luckasen
Dennis G
DG
Larson
Frank A
FA
Dinenno
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D001783:Blood Flow Velocity; D001916:Brachial Artery / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D016022:Case-Control Studies; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000201:enzymology / Q000503:physiopathology; D005260:Female; D005542:Forearm / Q000098:blood supply*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006940:Hyperemia / Q000201:enzymology* / Q000503:physiopathology; D007261:Infusions, Intra-Arterial; D008297:Male; D008833:Microcirculation; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010991:Plethysmography; D026902:Potassium Channel Blockers / Q000008:administration & dosage; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D012039:Regional Blood Flow; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D014664:Vasodilation; D014665:Vasodilator Agents / Q000008:administration & dosage; D055815:Young Adult
D016861:Cyclooxygenase Inhibitors; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011453:Prostaglandins; D014665:Vasodilator Agents; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000254:Sodium-Potassium-Exchanging ATPase
blood flow regulation; hyperpolarization; ischemia; vasodilation