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(Circulation. 2001;104:2177.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Bradykinin Contributes to the Vasodilator Effects of Chronic Angiotensin-Converting Enzyme Inhibition in Patients With Heart Failure

Fraser N. Witherow, MB, ChB, MRCP; Ahmed Helmy, MB, ChB, PhD; David J. Webb, MD, FRCP, FRCPE, FFPM, FMed Sci; Keith A.A. Fox, BSc (Hons), MB, ChB, FRCP, FESC; David E. Newby, BSc (Hons), PhD, BM, DM, MRCP

From the Department of Cardiovascular Research, University of Edinburgh, Royal Infirmary of Edinburgh and Department of Clinical Pharmacology, Western General Hospital (D.J.W.), Edinburgh, Scotland, UK.

Correspondence to Dr D.E. Newby, Cardiovascular Research, Department of Cardiology, Royal Infirmary, Lauriston Place, Edinburgh EH3 9YW, Scotland, UK. E-mail d.e.newby{at}ed.ac.uk

Background— Bradykinin, an endogenous vasodilator peptide, is metabolized by ACE. The aims of the present study were to determine the doses of B9340, a bradykinin receptor antagonist, that inhibit vasodilatation to exogenous bradykinin and to assess the contribution of bradykinin to the maintenance of basal vascular tone in patients with heart failure receiving chronic ACE inhibitor therapy.

Methods and Results— Forearm blood flow was measured using bilateral venous occlusion plethysmography. On three occasions in a double-blind randomized manner, 8 healthy volunteers received intrabrachial infusions of placebo or B9340 (at 4.5 and 13.5 nmol/min). On each occasion, placebo or B9340 was coinfused with bradykinin (30 to 3000 pmol/min) and substance P (4 to 16 pmol/min). B9340 caused no change in basal FBF but produced dose-dependent inhibition of the vasodilatation to bradykinin (P<0.001) but not substance P. The effects of bradykinin antagonism were studied in 17 patients with NYHA grade II through IV heart failure maintained on chronic ACE inhibitor therapy. Incremental doses of B9340, but not HOE-140, produced a dose-dependent vasoconstriction (P=0.01). After withdrawal of ACE inhibitor therapy, B9340 produced no significant change in forearm blood flow. After reinstitution of therapy, B9340 again resulted in vasoconstriction (P<0.03).

Conclusions— B9340 is a potent and selective inhibitor of bradykinin-induced vasodilatation. Bradykinin does not contribute to the maintenance of basal peripheral arteriolar tone in healthy humans or patients with heart failure but contributes to the vasodilatation associated with chronic ACE inhibitor therapy in patients with heart failure via the B₁ receptor.

Key Words: bradykinin • heart failure • blood flow