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

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substance P (2 to 8 pmol/min), and sodium nitroprusside (1 to 4 pmol/min) were infused, and venous blood samples were withdrawn from both forearms for estimation of fibrinolytic variables.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 g/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. (J Am Coll Cardiol 2002;40: 961–6) © 2002 by the American College of Cardiology Foundation