Treatment with endothelin-receptor antagonists increases NOS activity in hypercholesterolemia

C. Burcin Taner, Sandra R. Severson, Patricia Best, Amir Lerman, Virginia M Miller

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)816-820
Number of pages5
JournalJournal of Applied Physiology
Volume90
Issue number3
StatePublished - 2001

Fingerprint

Hypercholesterolemia
Nitric Oxide
Swine
Endothelin-1
Endothelium
Endothelial Cells
Cholesterol
Atherogenic Diet
Endothelin Receptors
Messenger RNA
Nitric Oxide Synthase Type III
Thoracic Aorta
Coronary Vessels
Endothelin Receptor Antagonists

Keywords

  • Atherosclerosis
  • Endothelial cells
  • Endothelin-1
  • Lipidemia
  • Messenger ribonucleic acid

ASJC Scopus subject areas

  • Physiology
  • Endocrinology
  • Orthopedics and Sports Medicine
  • Physical Therapy, Sports Therapy and Rehabilitation

Cite this

Treatment with endothelin-receptor antagonists increases NOS activity in hypercholesterolemia. / Taner, C. Burcin; Severson, Sandra R.; Best, Patricia; Lerman, Amir; Miller, Virginia M.

In: Journal of Applied Physiology, Vol. 90, No. 3, 2001, p. 816-820.

Research output: Contribution to journalArticle

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