ENDOTHELIAL FUNCTION
Potentiation of bradykinin-induced tissue plasminogen activator release by angiotensin-converting enzyme inhibition
Catherine Labinjoh, BSc, MB, ChB (Hons), MRCP*,
David E. Newby, BA, BSc, PhD, DM, (Hons), BM, MRCP*,*  ,
M. Paola Pellegrini, MB, ChB*,
Neil R. Johnston, MSc*,
Nicholas A. Boon, BA, MB, MA, MD, BChir, FRCP and
David J. Webb, MB, MD, DSc, FRCP, FFPM, FMedSci*
* Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, United Kingdom
Department of Cardiology, Royal Infirmary, Lauriston Place, Edinburgh, United Kingdom
Manuscript received April 18, 2001;
revised manuscript received June 29, 2001,
accepted July 19, 2001.
* Reprint requests and correspondence: Dr. David E. Newby, Cardiovascular Research, Department of Cardiology, Royal Infirmary, Lauriston Place, Edinburgh, EH3 9YW, Scotland, UK
d.e.newby{at}ed.ac.uk
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 µg/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.
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Abbreviations and Acronyms
| | ACE | = angiotensin-converting enzyme | | ANOVA | = analysis of variance | | AT1 | = angiotensin II type 1 | | PAI-1 | = plasminogen activator inhibitor type 1 | | t-PA | = tissue plasminogen activator |
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