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Fig. 1. Effect of acute ascorbic acid (AA) infusion on mean response time (MRT). A: change in forearm vascular conductance (FVC) averaged in 3-s bins during
5 min of dynamic forearm exercise. Data from a representative healthy control before AA infusion (Trial 1). B: Lean (n 13), Obese (n 10), metabolic
syndrome (MetSyn) (n 9). MRT was not different between groups (main effect of group: P 0.26). MRT was not altered when AA was infused (Trial 2),
compared with exercise alone (Trial 1) (main effect of AA: P 0.50). C: change in MRT with AA infusion () was not different between groups (interaction
between group and AA: P 0.90) although individual responses were variable (a negative value indicates MRT decreased with AA infusion).
RESULTS
Subject characteristics. Subject characteristics are summarized in Table 1. Fourteen adults with MetSyn, 10 obese, and
15 lean healthy adults completed the present study (74% White
non-Hispanic, 5% White Hispanic, 13% Asian American, 3%
Table 1. Subject demographics
Sex, M/F
Age, yr
Height, cm
Weight, kg
BMI, kg/m2
Waist, cm
Body fat, %
Total forearm mass, g
Lean forearm mass, g
MVC, kg
MABP, mmHg
Glucose, mg/dl
Insulin, U/ml
HOMA-IR, AU
QUICKI, AU
Total cholesterol, mg/dl
Triglyceride, mg/dl
HDL, mg/dl
LDL, mg/dl
CRP, mg/l
TBARS, MDA units
TAC, Trolox, M
TAC increase with AA, %
Physical activity, kcal/wk
Lean
Obese
MetSyn
12/3
30 3
174 2
70 3
23 1
79 3
22 2
1028 63
970 59
39 2
90 2
81 3
12 1
31
0.34 0.01
151 8
76 7
46 4
91 6
0.4 0.1
1.5 0.2
3.9 1.5
224 97
2354 523
8/2
33 3
174 3
110 7*
36 2*
114 4*
40 2*
1436 93*
1063 68
46 3
98 4
75 3
31 9*
62
0.31 0.01
162 14
98 12
32 4
115 8
1.4 0.4
1.5 0.2
2.3 0.1
137 34
1528 233
10/4
33 3
176 3
122 8*
39 2*
119 5*
41 2*
1457 175
1040 114
41 3
105 2*
92 5
43 9*
10 2*
0.28 0.01*
173 12
189 28*
37 4
99 10
2.1 0.5*
1.9 0.3
2.2 0.2
166 57
1889 461
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Obese
MetSyn
105 2*
106 3*
109 3*
0.43 0.02
0.45 0.02
0.46 0.02
14 2*
43 7*
46 7*
13 3*
41 6*
43 6*
Values are means SE. Lean (n 14), Obese (n 10), MetSyn (n 13)
(2 subjects did not complete all 15 min of exercise). Main effect of group:
*P 0.05 vs. Lean. Main effect of exercise: P 0.05 vs. Rest.
Table 3. Steady-state responses to 5-min forearm exercise before and after intra-arterial infusion of AA, Trial 1 (Pre-AA)
vs. Trial 2 (Post-AA)
Lean
Pre-AA
Obese
Post-AA
Pre-AA
MetSyn
Post-AA
Pre-AA
Post-AA
101 3
101 3
104 3
105 3
105 2*
106 2*
113 3*
112 3*
0.44 0.02*
0.46 0.02*
0.44 0.02*
0.47 0.02*
0.44 0.02*
0.46 0.02*
0.44 0.02*
0.46 0.02*
92
33 5
12 2
37 4
16 3*
45 6*
15 2*
43 5*
92
33 5
11 2
36 4
15 3*
42 6*
14 2*
39 5*
Values are means SE. Lean (n 15), Obese (n 10), MetSyn (n 14). Main effect of group: *P 0.05 vs. Lean, P 0.05 vs. Obese. Main effect
of AA: P 0.05 versus Pre AA.
AJP-Heart Circ Physiol doi:10.1152/ajpheart.00312.2014 www.ajpheart.org
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30
20
20
10
10
0
MetSyn
Lean
25
20
30
10
10
5
0
-10
-5
-20
-10
-30
Obese
Lean
MetSyn
Obese
MetSyn
DISCUSSION
60
10
50
MetSyn
20
Obese
15
Lean
70
0
Obese
-15
40
30
Lean
FVC (mL/min*100mmHg*100g)
40
30
20
-10
-20
-30
-40
10
-50
C-Reactive Protein
AJP-Heart Circ Physiol doi:10.1152/ajpheart.00312.2014 www.ajpheart.org
C-Reactive Protein
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modified the observed relationship between low physical activity and increased steady-state vasodilation with AA. Future
studies are necessary to explore this idea, in addition to
examining the effect of initiation of an exercise training program in sedentary individuals.
Experimental considerations. As summarized above, group
data indicate that increasing total antioxidant capacity with AA
infusion does not alter time course (MRT) or magnitude (
FVC) of vasodilator responses to moderate-intensity, dynamic
forearm exercise. This observation may be the result of the
relatively young age and likely short disease duration in the
present study population, resulting in only small group differences in baseline measures of systemic oxidative stress, antioxidant capacity, and inflammation (Table 1). However, the
range of individual responses to exercise and AA infusion
within the present data, independent of group, is consistent
with the concept of unique physiological phenotypes. Specifically, when the change in vascular responses to acute AA
infusion was examined, MRT and FVC to exercise increased,
decreased, or did not change (Figs. 1C, and 2, B and D).
Furthermore, our data suggest that systemic measures of oxidative stress may not be representative of what is occurring
locally within the skeletal muscle vasculature, and thus large
differences in systemic oxidative stress may not be necessary
to observe impairments in vascular control and/or improvements with infusion of AA. Thus physiological changes likely
occur in some subjects very early in the disease process, before
large impairments in standard clinical measures. Considering
that ROS scavenging improves exercise-mediated vasodilation
in a group of healthy older adults (21) and endothelial-dependent vasodilation in older obese adults (32), our data indicate a
complex transition between early disease processes and advancing age, with the potential for age-by-disease and/or lifestyle interactions. These speculations require more rigorous
testing both acutely and longitudinally.
It is important to note that CRP is a marker of systemic
inflammation and CRP elevations likely occur in response to
disturbances in IL-1, TNF-, and IL-6 signaling. Thus CRP may
not be mediating the observed impairments in MRT to dynamic
handgrip exercise and may not be an appropriate direct target for
future therapies (22); however, our results are suggestive of the
contribution of an inflammatory pathway in observed responses.
Furthermore, although we observed significant increases in TAC,
we did not directly measure changes in ROS during study interventions. Taken together, future studies will be necessary to better
understand the specific mechanisms behind inflammation-mediated impairments in MRT and the direct effect of ROS scavenging
(both acute and chronic therapies) on measures of exercisemediated vasodilation.
Conclusion. In summary, our findings add to the growing
body of knowledge indicating that the ability to achieve steadystate vasodilation in response to moderate-intensity, dynamic
forearm exercise is not impaired by obesity or MetSyn in
younger (32 yr) humans. Despite preserved exercise responses, factors linked to cardiovascular disease risk (e.g.,
inflammation) might alter control mechanisms important to
exercise-mediated vasodilation. Furthermore, the variety of
both time-course and steady-state vasodilator responses to
exercise, as well as the range of individual responses to acute
AA infusion, suggest that a normal exercise response can be
achieved by numerous physiological mechanisms, some of which
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