title: Increased activity of endogenous endothelin in patients with hypercholesterolemia.
abstract: OBJECTIVE
  We sought to assess the activity of endogenous endothelin-1 (ET-1) in hypercholesterolemic patients using antagonists of ET-1 receptors.
  
  
  BACKGROUND
  Endothelial dysfunction in hypercholesterolemic patients may contribute to their risk of premature atherosclerosis. Endothelin, a peptide released by endothelial cells, may be involved in this process by activating smooth muscle cell mitogenesis and leukocyte adhesion.
  
  
  METHODS
  Forearm blood flow (FBF) responses (strain-gauge plethysmography) to intra-arterial infusion of a selective blocker of ETA receptors (BQ-123) and, on a separate occasion, to ET-1 were measured in 12 hypercholesterolemic patients and 12 normal control subjects. In addition, on a different day, six hypercholesterolemic patients received co-infusion of BQ- 123 and BQ-788 (a selective blocker of ETB receptors).
  
  
  RESULTS
  In normal subjects, BQ-123 did not significantly modify FBF from baseline (p = 0.78); however, in hypercholesterolemic patients, BQ-123 administration resulted in a significant vasodilator response (p < 0.001). Administration of exogenous ET-1 resulted in similar vasoconstrictor responses in patients (37%) and control subjects (35%) (p = 0.83). In hypercholesterolemic patients, the vasodilator response to selective ETA blockade was reversed by nonselective blockade of ET-1 receptors obtained by co-infusion of BQ-123 and BQ-788.
  
  
  CONCLUSIONS
  The vascular activity of endogenous ET-1 is enhanced in hypercholesterolemic patients, whereas their sensitivity to exogenous ET-1 is unchanged. These findings suggest increased production of ET-1, which may participate in the pathophysiology of vascular disease characteristic of hypercholesterolemia.
authors.affiliation: Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1650, USA.
authors.forename: C
authors.initials: C
authors.lastname: Cardillo
authors.forename: C M
authors.initials: CM
authors.lastname: Kilcoyne
authors.forename: R O
authors.initials: RO
authors.lastname: Cannon
authors.forename: J A
authors.initials: JA
authors.lastname: Panza
mesh_terms: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012039:Regional Blood Flow
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B