Abstract
We hypothesized that transient high-glucose concentration interferes with mediation by nitric oxide (NO) of flow-induced dilation (FID) of arterioles due to enhanced production of superoxide. In isolated, pressurized (80 mmHg) rat gracilis muscle arterioles (∼130 μm) after transient high-glucose treatment (tHG; incubation with 30 mM glucose for 1 h), FID was reduced (maximum: control, 38 ± 4%; after tHG, 17 ± 3%), which was not further diminished by the NO synthase (NOS) inhibitor N ω -nitro- L-arginine methyl ester (L-NAME; 18 ± 2%). Correspondingly, an enhanced polyethylene-glycol-SOD (PEG-SOD)-sensitive superoxide production was detected after tHG in carotid arteries by dihydroethydine (DHE) staining. Presence of PEG-SOD during tHG prevented the reduction of FID (41 ± 3%), which could be inhibited by L-NAME (20 ± 4%). Administration of PEG-SOD after tHG did not prevent the reduction of FID (22 ± 3%). Sepiapterin, a precursor of the NO synthase cofactor tetrahydrobiopterin (BH 4 ), administered during tHG did not prevent the reduction of FID (maximum, 15 ± 5%); however, it restored FID when administered after tHG (32 ± 4%). Furthermore, inhibition of either glycolysis by 2-deoxyglucose or mitochondrial complex II by 2-thenoyltrifluoroacetone reduced the tHG-induced DHE-detectable enhanced superoxide production in carotid arteries and prevented FID reduction in arterioles (39 ± 5 and 35 ± 2%). Collectively, these findings suggest that in skeletal muscle arterioles, a transient elevation of glucose via its increased metabolism, elicits enhanced production of superoxide, which decreases the bioavailability of NO and the level of the NOS cofactor BH 4 , resulting in a reduction of FID mediated by NO.
| Original language | English (US) |
|---|---|
| Journal | American Journal of Physiology - Heart and Circulatory Physiology |
| Volume | 287 |
| Issue number | 2 56-2 |
| DOIs | |
| State | Published - Aug 1 2004 |
| Externally published | Yes |
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Keywords
- 2-deoxyglucose
- Arteriole
- Glycolysis
- Mitochondrial complex II
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
- Physiology (medical)
Cite this
Microvascular dysfunction after transient high glucose is caused by superoxide-dependent reduction in the bioavailability of NO and BH 4 . / Bagi, Zsolt; Toth, Erika; Koller, Akos; Kaley, Gabor.
In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 287, No. 2 56-2, 01.08.2004.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Microvascular dysfunction after transient high glucose is caused by superoxide-dependent reduction in the bioavailability of NO and BH 4
AU - Bagi, Zsolt
AU - Toth, Erika
AU - Koller, Akos
AU - Kaley, Gabor
PY - 2004/8/1
Y1 - 2004/8/1
N2 - We hypothesized that transient high-glucose concentration interferes with mediation by nitric oxide (NO) of flow-induced dilation (FID) of arterioles due to enhanced production of superoxide. In isolated, pressurized (80 mmHg) rat gracilis muscle arterioles (∼130 μm) after transient high-glucose treatment (tHG; incubation with 30 mM glucose for 1 h), FID was reduced (maximum: control, 38 ± 4%; after tHG, 17 ± 3%), which was not further diminished by the NO synthase (NOS) inhibitor N ω -nitro- L-arginine methyl ester (L-NAME; 18 ± 2%). Correspondingly, an enhanced polyethylene-glycol-SOD (PEG-SOD)-sensitive superoxide production was detected after tHG in carotid arteries by dihydroethydine (DHE) staining. Presence of PEG-SOD during tHG prevented the reduction of FID (41 ± 3%), which could be inhibited by L-NAME (20 ± 4%). Administration of PEG-SOD after tHG did not prevent the reduction of FID (22 ± 3%). Sepiapterin, a precursor of the NO synthase cofactor tetrahydrobiopterin (BH 4 ), administered during tHG did not prevent the reduction of FID (maximum, 15 ± 5%); however, it restored FID when administered after tHG (32 ± 4%). Furthermore, inhibition of either glycolysis by 2-deoxyglucose or mitochondrial complex II by 2-thenoyltrifluoroacetone reduced the tHG-induced DHE-detectable enhanced superoxide production in carotid arteries and prevented FID reduction in arterioles (39 ± 5 and 35 ± 2%). Collectively, these findings suggest that in skeletal muscle arterioles, a transient elevation of glucose via its increased metabolism, elicits enhanced production of superoxide, which decreases the bioavailability of NO and the level of the NOS cofactor BH 4 , resulting in a reduction of FID mediated by NO.
AB - We hypothesized that transient high-glucose concentration interferes with mediation by nitric oxide (NO) of flow-induced dilation (FID) of arterioles due to enhanced production of superoxide. In isolated, pressurized (80 mmHg) rat gracilis muscle arterioles (∼130 μm) after transient high-glucose treatment (tHG; incubation with 30 mM glucose for 1 h), FID was reduced (maximum: control, 38 ± 4%; after tHG, 17 ± 3%), which was not further diminished by the NO synthase (NOS) inhibitor N ω -nitro- L-arginine methyl ester (L-NAME; 18 ± 2%). Correspondingly, an enhanced polyethylene-glycol-SOD (PEG-SOD)-sensitive superoxide production was detected after tHG in carotid arteries by dihydroethydine (DHE) staining. Presence of PEG-SOD during tHG prevented the reduction of FID (41 ± 3%), which could be inhibited by L-NAME (20 ± 4%). Administration of PEG-SOD after tHG did not prevent the reduction of FID (22 ± 3%). Sepiapterin, a precursor of the NO synthase cofactor tetrahydrobiopterin (BH 4 ), administered during tHG did not prevent the reduction of FID (maximum, 15 ± 5%); however, it restored FID when administered after tHG (32 ± 4%). Furthermore, inhibition of either glycolysis by 2-deoxyglucose or mitochondrial complex II by 2-thenoyltrifluoroacetone reduced the tHG-induced DHE-detectable enhanced superoxide production in carotid arteries and prevented FID reduction in arterioles (39 ± 5 and 35 ± 2%). Collectively, these findings suggest that in skeletal muscle arterioles, a transient elevation of glucose via its increased metabolism, elicits enhanced production of superoxide, which decreases the bioavailability of NO and the level of the NOS cofactor BH 4 , resulting in a reduction of FID mediated by NO.
KW - 2-deoxyglucose
KW - Arteriole
KW - Glycolysis
KW - Mitochondrial complex II
UR - http://www.scopus.com/inward/record.url?scp=3242732165&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=3242732165&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00074.2004
DO - 10.1152/ajpheart.00074.2004
M3 - Article
C2 - 15044190
AN - SCOPUS:3242732165
VL - 287
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
SN - 0363-6135
IS - 2 56-2
ER -