CLINICAL STUDY: ANGIOTENSIN ANTAGONISTS AND HEART FAILURE
Marked bradykinin-induced tissue plasminogen activator release in patients with heart failure maintained on long-term angiotensin-converting enzyme inhibitor therapy
Fraser N. Witherow, MB, ChB, MRCP*,
Pamela Dawson, HNC ,
Christopher A. Ludlam, MB, ChB, PhD, FRCP, FRCPath,
Keith A. A. Fox, BSc (Hons), MB, ChB, FRCP, FESC* and
David E. Newby, BA, BSc (Hons), PhD, BM, DM, MRCP*,*
* Cardiovascular Research, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, Scotland, United Kingdom
Department of Haematology, Royal Infirmary of Edinburgh, Edinburgh, Scotland, United Kingdom
Manuscript received February 25, 2002;
revised manuscript received April 22, 2002,
accepted May 7, 2002.
* Reprint requests and correspondence: Dr. David E. Newby, Cardiovascular Research, Royal Infirmary of Edinburgh, Lauriston Place, Edinburgh, Scotland EH3 9YW, United Kingdom
d.e.newby{at}ed.ac.uk
OBJECTIVES: 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substance P (2 to 8 pmol/min), and sodium nitroprusside (1 to 4 pmol/min) were infused, and venous blood samples were withdrawn from both forearms for estimation of fibrinolytic variables.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  4.5 µg/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.
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Abbreviations and Acronyms
| | ACE | | angiotensin-converting enzyme | | ANOVA | | analysis of variance | | d.f. | | degree of freedom | | HF | | heart failure | | MI | | myocardial infarction | | PAI-1 | | plasminogen activator inhibitor type 1 | | t-PA | | tissue-type plasminogen activator |
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