Abstract
In experimental hypercholesterolemia, endothelium-dependent relaxations decrease, as does endothelial immunoreactivity for nitric oxide (NO) synthase (NOS; eNOS) in coronary arteries. Systemic levels of NO also decrease with concomitant elevations in systemic circulating levels of endothelin (ET)-1. Chronic treatment of hypercholesterolemic pigs with ET-receptor antagonists increases circulating NO and improves endothelium-dependent relaxations. Mechanisms causing these increases are not known. Therefore, experiments were designed to test the hypothesis that chronic administration of ET-receptor antagonists to hypercholesterolemic pigs increases NO production through increases in NOS activity. Female juvenile pigs were fed a 2% cholesterol atherogenic diet and were randomly allocated to receive no treatment (controls), a selective ETA-receptor antagonist (ABT-624), or a combined ETA + ETB-receptor antagonist (RO-48-5695) daily for 12 wk. After 12 wk, endothelial cells from thoracic aorta were prepared for measurement of eNOS mRNA or eNOS activity. Total cholesterol, lowdensity-lipoprotein cholesterol, and concentrations of ET-1 were significantly higher in all three groups at 12 wk compared with baseline levels. Circulating plasma-oxidized products of NO (NOx) increased with ET-receptor blockade. NOS mRNA was similar among groups. Total and Ca-dependent NOS activity was significantly higher in aortic endothelial cells from the ETA + ETB-treated pigs compared with those treated with ETA antagonist alone. These results suggest that changes in systemic NOx after chronic inhibition of ETA + ETB receptors in hypercholesterolemia may result from posttranscriptional changes in NOS.
Original language | English (US) |
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Pages (from-to) | 816-820 |
Number of pages | 5 |
Journal | Journal of applied physiology |
Volume | 90 |
Issue number | 3 |
DOIs | |
State | Published - 2001 |
Keywords
- Atherosclerosis
- Endothelial cells
- Endothelin-1
- Lipidemia
- Messenger ribonucleic acid
ASJC Scopus subject areas
- Physiology
- Physiology (medical)