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. 2013 Oct;20(7):662-9.
doi: 10.1111/micc.12065.

Impaired vascular KATP function attenuates exercise capacity in obese zucker rats

Silu Lu  1 , Lusha Xiang, John S Clemmer, Andrew R Gowdey, Peter N Mittwede, Robert L Hester
Affiliations

Impaired vascular KATP function attenuates exercise capacity in obese zucker rats

Silu Lu et al. Microcirculation. 2013 Oct.

Abstract

Objective: Obese subjects exhibit decreased exercise capacity (VO2max ). We have shown that vascular KATP channel mediates arteriolar dilation to muscle contraction. We hypothesize that exercise capacity is decreased in obesity due to impaired vascular KATP function.

Methods: The VO2max was measured in LZR and OZR by treadmill running before and following treatment with the KATP blocker glibenclamide i.p. One week later, the spinotrapezius muscle was prepared for in vivo microscopy. Arcade arteriolar diameters were measured following muscle contraction or application of the KATP opener cromakalim before and after glibenclamide application. In additional animals, LZR and OZR were treated with apocynin for five weeks. VO2max and arteriolar dilation experiments were repeated.

Results: The OZR exhibited decreased VO2max , functional and cromakalim-induced vasodilation as compared with LZR. Glibenclamide had no effect on VO2max and functional vasodilation in OZR, but significantly inhibited responses in LZR. Vascular superoxide levels and NADPH oxidase activity were increased in OZR, but reduced in apocynin-treated OZR. Apocynin increased the VO2max , functional and cromakalim-induced vasodilation in OZR with no effect in LZR.

Conclusions: Exercise capacity is dependent on vascular KATP channel function. The reduced exercise capacity in OZR appears to be due in part to superoxide-mediated impairment in vascular KATP function.

Keywords: KATP channels; NADPH oxidase; obese; superoxide; vascular.

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Figures

Figure 1
Figure 1. Oral glucose tolerance test in LZR and OZR with and without apocynin treatment
The fasting glucose levels were not significantly different between LZR and OZR both control and apocynin-treated groups. After gavage with a glucose solution, OZR exhibited significantly higher hyperglycemia compared with LZR in both control and apocynin-treated group (*, p < 0.05; #, p < 0.05). Apocynin treatment has no effect on insulin sensitivity in both LZR and OZR. (LZR control, n = 5; OZR control, n = 5; LZR apocynin, n = 4; OZR apocynin, n = 6).
Figure 2
Figure 2. The effect of apocynin on VO2max in LZR and OZR before and following glibenclamide application (i.p.)
OZR exhibited an impaired VO2max (*, p<0.05 vs. LZR). Apocynin enhanced VO2max in OZR significantly (#, p<0.05 vs. OZR) but did not normalize it (+, p<0.05 vs. LZR with apocynin). Apocynin had no effect on LZR. Glibenclamide inhibited VO2max in all groups except in OZR control (&, p<0.05 vs. OZR with apocynin). OZR exhibited a less functional vasodilation after glibenclamide treatment in control group ($, p<0.05 vs. LZR+glibenclamide; n=5 for all groups).
Figure 3
Figure 3. The effect of apocynin on functional vasodilation in spinotrapezius muscle in LZR and OZR with or without glibenclamide application
OZR exhibited blunt functional vasodilation (*, p<0.05 vs. LZR). Apocynin enhanced functional vasodilation in OZR significantly (#, p<0.05 vs. OZR) but did not normalize it (+, p<0.05 vs. LZR with apocynin). Apocynin had no effect in LZR. Glibenclamide pretreatment (30 min) inhibited functinal vasodilation in all groups except in OZR control (&, p<0.05 vs. OZR with apocynin). OZR exhibited a less functional vasodilation after glibenclamide pretreatment in both control and apocynin groups ($, p<0.05 vs. LZR+glibenclamide; @, p<0.05 vs. LZR with apocynin+glibenclamide, n=7 for LZR, n=5 for OZR, n=6 for both LZR and OZR with apocynin).
Figure 4
Figure 4. Cromakalim induced vasodilation in spinotrapezius muscle in LZR and OZR with or without apocynin
Cromakalim (0.01, 0.1, and 1 μM) induced vasodilation in concentration-dependent manner. OZR exhibited an impaired vasodilation response to cromakalim (*, p<0.05 vs. LZR). Apocynin significantly enhanced cromakalim-induced vasodilation in OZR (#, p<0.05 vs. OZR) but did not normalize it (+, p<0.05 vs. LZR with apocynin; n=7 for LZR, n=5 for OZR, n=6 for both LZR and OZR with apocynin)
Figure 5
Figure 5. Femoral vascular NADPH oxidase activity in LZR and OZR with or without apocynin treatment
Basal superoxide levels were subtracted from the NADPH-stimulated superoxide levels and normalized by protein concentration. OZR exhibited significant high NADPH oxidase activity (*, p<0.05 vs. LZR). Apocynin treatment reduced NADPH oxidase activity in OZR significantly and had no effect on LZR (#, p<0.05 vs. OZR; n=6 for LZR, n=5 for OZR, n=6 for both LZR and OZR with apocynin treatment).
Figure 6
Figure 6. Superoxide levels in LZR and OZR with or without apocynin treatment
Confocal images obtained using a laser scanning confocal microscopy from DHE-treated aortic segments (split longitudinally). Superoxide levels between control and apocynin-treated LZR and OZR were compared. OZR had increased fluorescence compared with LZR (*, p<0.05 vs. LZR control). Apocynin treatment significantly reduced the fluorescence in OZR (#, p<0.05 vs. OZR control) but failed to normalize the superoxide level ((*, p<0.05 vs. LZR apocynin-treated; n=7 for LZR, n=5 for OZR, n=6 for both LZR and OZR with apocynin).)
See this image and copyright information in PMC

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