title: Marked bradykinin-induced tissue plasminogen activator release in patients with heart failure maintained on long-term angiotensin-converting enzyme inhibitor therapy.
abstract: OBJECTIVE
  The aim of the present study was to assess the contribution of angiotensin-converting enzyme (ACE) inhibitor therapy to bradykinin-induced tissue-type plasminogen activator (t-PA) release in patients with heart failure (HF) secondary to ischemic heart disease.
  
  
  BACKGROUND
  Bradykinin is a potent endothelial cell stimulant that causes vasodilatation and t-PA release. In large-scale clinical trials, ACE inhibitor therapy prevents ischemic events.
  
  
  METHODS
  Nine patients with symptomatic HF were evaluated on two occasions: during and following seven-day withdrawal of long-term ACE inhibitor therapy. Forearm blood flow was measured using bilateral venous occlusion plethysmography. Intrabrachial bradykinin (30 to 300 pmol/min), substance P (2 to 8 pmol/min), and sodium nitroprusside (1 to 4 pmol/min) were infused, and venous blood samples were withdrawn from both forearms for estimation of fibrinolytic variables.
  
  
  RESULTS
  On both study days, bradykinin and substance P caused dose-dependent vasodilatation and release of t-PA from the infused forearm (p < 0.05 by analysis of variance [ANOVA]). Long-term ACE inhibitor therapy caused an increase in forearm vasodilatation (p < 0.05 by ANOVA) and t-PA release (p < 0.001 by ANOVA) during bradykinin, but not substance P, infusion. Maximal local plasma t-PA activity concentrations approached 100 IU/ml, and maximal forearm protein release was approximately 4.5 microg/min.
  
  
  CONCLUSIONS
  Long-term ACE inhibitor therapy augments bradykinin-induced peripheral vasodilatation and local t-PA release in patients with HF due to ischemic heart disease. Local plasma t-PA activity concentrations approached those seen during systemic thrombolytic therapy for acute myocardial infarction. This may contribute to the primary mechanism of the anti-ischemic effects associated with long-term ACE inhibitor therapy.
authors.affiliation: Cardiovascular Research, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors.forename: Fraser N
authors.initials: FN
authors.lastname: Witherow
authors.forename: Pamela
authors.initials: P
authors.lastname: Dawson
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ludlam
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
mesh_terms: D000368:Aged; D001920:Bradykinin / Q000494:pharmacology*; D005260:Female; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000627:therapeutic use*; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000627:therapeutic use*; D010991:Plethysmography; D013373:Substance P; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014666:Vasomotor System / Q000187:drug effects
chemical_list: D010446:Peptide Fragments; C068142:glyceraldehyde 3-phosphate dehydrogenase (304-313); D013373:Substance P; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D010959:Tissue Plasminogen Activator; D001920:Bradykinin