| Item type: | Article | ||||
|---|---|---|---|---|---|
| Journal or Publication Title: | American Journal of Physiology-Heart and Circulatory Physiology | ||||
| Publisher: | AMER PHYSIOLOGICAL SOC | ||||
| Place of Publication: | BETHESDA | ||||
| Volume: | 307 | ||||
| Number of Issue or Book Chapter: | 8 | ||||
| Page Range: | H1093-H1102 | ||||
| Date: | 2014 | ||||
| Institutions: | Medicine > Lehrstuhl für Innere Medizin II | ||||
| Identification Number: |
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| Keywords: | ACTIVATED POTASSIUM CHANNELS; MYOENDOTHELIAL GAP-JUNCTIONS; CA2+-ACTIVATED K+ CHANNELS; EDHF-TYPE RELAXATION; WORKING GROUP-REPORT; HYPERPOLARIZING FACTOR; ENDOTHELIAL DYSFUNCTION; NITRIC-OXIDE; EPOXYEICOSATRIENOIC ACIDS; HEME OXYGENASE; diabetes; calcium-activated potassium channel; vasodilation; endothelium; nitric oxide; endothelium-derived hyperpolarization; mesenteric artery | ||||
| Dewey Decimal Classification: | 600 Technology > 610 Medical sciences Medicine | ||||
| Status: | Published | ||||
| Refereed: | Yes, this version has been refereed | ||||
| Created at the University of Regensburg: | Yes | ||||
| Item ID: | 61068 |
Web of ScienceAbstract
Impaired endothelial function, which is dysregulated in diabetes, also precedes hypertension. We hypothesized that in Type 2 diabetes, the impaired endothelium-dependent relaxation is due to a loss of endothelium-derived hyperpolarization (EDH) that is regulated by impaired ion channel function. Zucker diabetic fatty (ZDF), Zucker heterozygote, and homozygote lean control rats were used as the ...
Abstract
Impaired endothelial function, which is dysregulated in diabetes, also precedes hypertension. We hypothesized that in Type 2 diabetes, the impaired endothelium-dependent relaxation is due to a loss of endothelium-derived hyperpolarization (EDH) that is regulated by impaired ion channel function. Zucker diabetic fatty (ZDF), Zucker heterozygote, and homozygote lean control rats were used as the experimental models in our study. Third-order mesenteric arteries were dissected and mounted on a pressure myograph; mRNA was quantified by RT-PCR and channel proteins by Western blotting. Under nitric oxide (NO) synthase and cyclooxygenase inhibition, endothelial stimulation with ACh fully relaxes control but not diabetic arteries. In contrast, when small-conductance calcium-activated potassium (K-Ca) channels and intermediate-and large-conductance K-Ca (I/BKCa) are inhibited with apamin and charybdotoxin, NO is able to compensate for ACh-induced relaxation in control but not in diabetic vessels. After replacement of charybdotoxin with 1-[(2-chlorophenyl)diphenylmethyl]-H-1-pyrazole (TRAM-34; IKCa inhibitor), ACh-induced relaxation in diabetic animals is attenuated. Specific inhibition with TRAM-34 or charybdotoxin attenuates ACh relaxation in diabetes. Stimulation with 1-ethyl-2-benzimidazolinone (IKCa activator) shows a reduced relaxation in diabetes. Activation of BKCa with 1,3-dihydro-1-[ 2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-H-2-benzimidazol-2-one NS619 leads to similar relaxations of control and diabetic arteries. RT-PCR and Western blot analysis demonstrate elevated mRNA and protein expression levels of IKCa in diabetes. Our results suggest that the compensatory effect of NO and EDH-associated, endothelium-dependent relaxation is reduced in ZDF rats. Specific blockade of IKCa with TRAM-34 reduces NO and EDH-type relaxation in diabetic rats, indicating an elevated contribution of IKCa in diabetic small mesenteric artery relaxation. This finding correlates with increased IKCa mRNA and protein expression in this vessel.
Metadata last modified: 19 Dec 2024 08:06
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