title: Treatment with endothelin-receptor antagonists increases NOS activity in hypercholesterolemia.
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 ET(A)-receptor antagonist (ABT-624), or a combined ET(A) + ET(B)-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, low-density-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 ET(A) + ET(B)-treated pigs compared with those treated with ET(A) antagonist alone. These results suggest that changes in systemic NOx after chronic inhibition of ET(A) + ET(B) receptors in hypercholesterolemia may result from posttranscriptional changes in NOS.
authors.affiliation: Department of Surgery, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
authors.forename: C B
authors.initials: CB
authors.lastname: Taner
authors.forename: S R
authors.initials: SR
authors.lastname: Severson
authors.forename: P J
authors.initials: PJ
authors.lastname: Best
authors.forename: A
authors.initials: A
authors.lastname: Lerman
authors.forename: V M
authors.initials: VM
authors.lastname: Miller
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004036:Diet, Atherogenic; D065128:Endothelin Receptor Antagonists; D004730:Endothelium, Vascular / Q000201:enzymology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006937:Hypercholesterolemia / Q000097:blood / Q000201:enzymology / Q000503:physiopathology*; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000235:genetics; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides / Q000494:pharmacology*; D013552:Swine; D014158:Transcription, Genetic / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
chemical_list: D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D065128:Endothelin Receptor Antagonists; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C118553:Ro 48-5695; D013449:Sulfonamides; D014280:Triglycerides; D002784:Cholesterol; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III