Potentiation of bradykinin-induced tissue plasminogen activator release by angiotensin-converting enzyme inhibition

C Labinjoh, D E Newby, M P Pellegrini, N R Johnston, N A Boon, D J Webb

Research output: Contribution to journalArticlepeer-review

Abstract

OBJECTIVES: The aim of the present study was to determine the effect of angiotensin-converting enzyme (ACE) inhibition on the local stimulated release of tissue plasminogen activator (t-PA) from the endothelium.

BACKGROUND: Angiotensin-converting enzyme inhibitor therapy may exert a beneficial effect on the endogenous fibrinolytic balance.

METHODS: Blood flow and plasma fibrinolytic factors were measured in both forearms of eight healthy males who received unilateral brachial artery infusions of the endothelium-dependent vasodilators substance P (2 to 8 pmol/min) and bradykinin (100 to 1,000 pmol/min), and the endothelium-independent vasodilator sodium nitroprusside (2 to 8 microg/min). These measurements were performed on each of three occasions following one week of matched placebo, quinapril 40 mg or losartan 50 mg daily administered in a double-blind randomized crossover design.

RESULTS: Sodium nitroprusside, substance P and bradykinin produced dose-dependent increases in the blood flow of infused forearm (analysis of variance [ANOVA], p < 0.001 for all). Although sodium nitroprusside did not affect plasma t-PA concentrations, they were increased dose-dependently in the infused forearm by substance P and bradykinin infusion (ANOVA, p < 0.001 for both). Bradykinin-induced release of active t-PA was more than doubled during treatment with quinapril in comparison to placebo or losartan (two-way ANOVA: p < 0.003 for treatment group, p < 0.001 for t-PA response and p = ns for interaction), whereas the substance P response was unaffected.

CONCLUSIONS: We have shown a selective and marked augmentation of bradykinin-induced t-PA release during ACE inhibition. These findings suggest that the beneficial clinical and vascular effects of ACE inhibition may, in part, be mediated through local augmentation of bradykinin-induced t-PA release.

Original languageEnglish
Pages (from-to)1402-8
Number of pages7
JournalJournal of the American College of Cardiology
Volume38
Issue number5
DOIs
Publication statusPublished - 1 Nov 2001

Keywords

  • Adult
  • Analysis of Variance
  • Angiotensin-Converting Enzyme Inhibitors
  • Blood Flow Velocity
  • Brachial Artery
  • Bradykinin
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Synergism
  • Endothelium, Vascular
  • Fibrinolysis
  • Forearm
  • Humans
  • Infusions, Intravenous
  • Isoquinolines
  • Losartan
  • Male
  • Nitroprusside
  • Plethysmography, Impedance
  • Substance P
  • Tetrahydroisoquinolines
  • Tissue Plasminogen Activator
  • Vasodilator Agents

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