Coronary endothelial function is preserved with chronic endothelin receptor antagonism in experimental hypercholesterolemia in vitro

Patricia Best, Lilach O Lerman, Juan C. Romero, Darcy Richardson, David Holmes, Amir Lerman

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Hypercholesterolemia is associated with increased circulating and tissue endothelin-1 immunoreactivity, decreased nitric oxide (NO) activity, and altered endothelial function. We tested the hypothesis that chronic endothelin receptor antagonism preserves endothelial function and increases NO in experimental porcine hypercholesterolemia. Pigs were randomized to 3 groups: Group 1, a 2% high-cholesterol (HC) diet alone (n=7); group 2, RO-48- 5695, a combined endothelin receptor antagonist, and an HC diet (n=8); and group 3, ABT-627, a selective endothelin-A receptor antagonist, and an HC diet (n= 8). Coronary epicardial and arteriolar endothelial function was determined by a dose-response relaxation to bradykinin (10-11 to 10-6 mol/L), in all groups and in pigs maintained on a normal diet. Plasma total oxidized products of NO (NO(x)) were determined by chemiluminescence at baseline and after 12 weeks. Bradykinin-stimulated coronary epicardial and arteriolar relaxation in group 1 was attenuated compared with normal-diet controls. This relaxation was normalized with endothelin receptor antagonism. Plasma NO(x) decreased after 12 weeks in group 1 (-74.8±5.5%). This decrease was attenuated in the endothelin receptor antagonist groups (group 2, - 28.2±15.0%; group 3, - 38.9±20.6%). Chronic endothelin receptor antagonism preserves coronary endothelial function and increases NO in hypercholesterolemia. This study supports a role of endothelin-1 in the regulation of NO activity and suggests a possible therapeutic role for endothelin receptor antagonists in hypercholesterolemia.

Original languageEnglish (US)
Pages (from-to)2769-2775
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume19
Issue number11
StatePublished - 1999

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Keywords

  • Coronary vessels
  • Endothelin receptors
  • Hypercholesterolemia
  • Nitric oxide
  • Oxidative stress

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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