Skeletal muscle blood flow and vascular conductance are enhanced in humans with high‐affinity hemoglobin during handgrip exercise in severe hypoxia
Authors: Wiggins Chad C. , Dominelli Paolo B. , Senefeld Jonathon W. , Shepherd John R.A. , Baker Sarah E. , Uchida Koji , Joyner Michael J. 
Published: April 2020

BackgroundIn humans, exercise tolerance is determined by the balance of diffusive and convective elements of oxygen transport. Mathematical models have suggested that alterations in hemoglobin‐oxygen (Hb‐O2) binding affinity (P50) have minimal effects of on oxygen delivery. However, there is limited experimental data in humans to evaluate these models during exercise in humans.PurposeWe sought to investigate skeletal muscle blood flow and vascular conductance (hyperemic response to exercise and hypoxia) during exercise in otherwise healthy participants with chronically high Hb‐O2 affinity (HAH). We hypothesized that patients with HAH would have a blunted hyperemic response to both handgrip and hypoxia due to the marked polycythemia that is typical in participants with HAH compared to controls.MethodsParticipants with HAH (n=6, 3 men, age= 37±12 yr, P50=15±2 mmHg) and control participants matched for age, sex, and BMI (CTL, n=5, 3 men, age=41±8 yr, and P50=26±1 mmHg) completed two intensities (10% and 20% maximal voluntary contraction (MVC)) of rhythmic handgrip exercise with a duty cycle of 1s contraction and 2s relaxation (20 contractions·min−1). Each exercise intensity was performed breathing three different gas mixtures: 21%, 15%, and 10% oxygen. Brachial artery mean blood velocity was measured using Doppler ultrasound. Beat‐by‐beat blood pressure was measured via arterial catheterization. Forearm blood flow (FBF) was calculated as the product of mean blood velocity (cm·s−1) and brachial artery cross‐sectional area (cm2) and expressed as milliliters per minute (mL·min−1), and forearm vascular conductance (FVC) was calculated as (FBF) × (mean arterial pressure)−1 × 100 and expressed as mL·min−1·mmHg−1. Data were analyzed using a three‐way ANOVA (Inspirate [21%, 15%, 10% O2], group [CTL, HAH], handgrip intensity [Rest, 10% and 20% MVC]).ResultsDuring normoxia (21% O2), groups were not different in FBF (P>0.05), FVC (P>0.05) or arterial saturation (SaO2, P=0.54). Similarly, the moderate hypoxia condition (15% O2), groups were not different in FBF (P>0.05), or FVC (P>0.05) despite a preservation in arterial saturation in HAH (SaO2, CTL: 89.0±0.7% vs. HAH: 95.1±1.7%, P<0.001). However, with more severe hypoxic exposure (10% O2), FBF and FVC were higher in HAH than controls during the 20% MVC exercise (P<0.05). HAH also had higher FBF (P<0.05) and trended towards higher FVC in the 10% MVC exercise (P=0.08). Interestingly, arterial saturation was drastically higher for HAH at the end of handgrip exercise (20% MVC) in 10% O2 (CTL: 69.2±4.5% vs. HAH: 89.1±1.4%, P<0.001).ConclusionAs predicted in mathematical models, Hb‐O2 binding affinity had little effect on skeletal muscle blood flow and forearm vascular conductance during light exercise under normoxic and moderate hypoxic conditions (21% and 15% O2). However, with a greater physiological stress to skeletal muscle O2 uptake in a more severe hypoxic condition (10% O2), participants with HAH, contrary to our initial hypothesis, had preserved arterial O2 saturation and a greater hyperemic response than controls.Support or Funding InformationThis work was supported by the NIH (5T32DK007352‐39 to CCW, R35HL139854 to MJJ)

Rest

10% MVC

20% MVC

FBF,mL·min−1

21% O2

CTL

87 ± 8

327 ± 25

589 ± 26

HAH

142 ± 19

420 ± 29

716 ± 68

15% O2

CTL

173 ± 61

357 ± 63

707 ± 62

HAH

156 ± 66

539 ± 111

930 ± 143

10% O2

CTL

154 ± 72

386 ± 81

668 ± 57

HAH

244 ± 133

703 ± 199*

932 ± 118*

FVC,mL·min−1·mmHg−1

21% O2

CTL

94 ± 9

356 ± 27

621 ± 24

HAH

130 ± 19

363 ± 25

617 ± 63

15% O2

CTL

187 ± 63

384 ± 54

758 ± 53

HAH

137 ± 44

453 ± 79

764 ± 226

10% O2

CTL

171 ± 71

431 ± 73

708 ± 67

HAH

221 ± 109

718 ± 136

917 ± 172
*

Abbreviations: FBF, forearm blood flow; FVC, forearm vascular conductance; MVC, maximal voluntary contraction; CTL, control group; HAH, high‐affinity Hb group. Values are presented as mean±SE.
* indicates significant difference (P<0.05) from CTL group at same %MVC.