Abstract 13409: Endothelium-Derived Hyperpolarizing Factor Contributes to Hypoxia-induced Skeletal Muscle Vasodilation in Humans
Background: Systemic hypoxia in humans leads to skeletal muscle vasodilation thereby preserving oxygen delivery to metabolically active tissue. Nitric oxide (NO) and adenosine are known to contribute to this vasodilation but pharmacological blocking studies suggest that other factors also play a role. Endothelium-derived hyperpolarizing factor (EDHF) may contribute to metabolic blood flow regulation in vivo and can be inhibited with the cytochrome P450 2C9 antagonist fluconazole (FLUC).
Hypothesis: Regional inhibition of EDHF with FLUC alone or in combination with the NO synthase antagonist NG-monomethyl-L-arginine (L-NMMA) attenuates hypoxia-induced vasodilation.
Methods: We determined total forearm blood flow (FBF, venous occlusion plethysmography), forearm vascular conductance (FVC, calculated as FBF/mean blood pressure × 100; units) and skin blood flow (laser Doppler) at baseline, during brachial artery infusion of FLUC alone (0.33 mg/min; trial 1) or in combination with L-NMMA (50 mg over 10 min; trial 2) before and during systemic hypoxia (inspired O2 10%, for 10 min each) in 12 healthy humans (age 27 ± 1 yrs, 7 female). The vascular responses in the infused (experimental) and untreated (control) forearms were compared.
Results: During normoxia, in the experimental forearm FLUC alone and FLUC + L-NMMA reduced FVC by 10% and 18%, respectively (P< 0.05 for both). During hypoxia and FLUC alone (trial 1; arterial pO2 37±1 mmHg), FVC increased by 1.76 ± 0.37 units in the control forearm but only by 0.95 ± 0.35 units in the experimental forearm (P< 0.05). During hypoxia and FLUC + L-NMMA (trial 2; arterial pO2 36±1 mmHg), FVC increased by 2.32 ± 0.51 units in the control forearm but only by 0.72 ± 0.22 units in the experimental forearm (P< 0.05). These effects were not due to changes in skin blood flow.
Conclusion: Regional inhibition of EDHF with and without simultaneous inhibition of NO synthesis increases basal skeletal muscle vascular tone and substantially attenuates the forearm vasodilator response to systemic hypoxia. This vasodilator effect of EDHF may be particularly relevant when other vasodilator systems are impaired.
- © 2011 by American Heart Association, Inc.