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

Abstract

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 (PϽ0.001) 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 (Pϭ0.01). After withdrawal of ACE inhibitor therapy, B9340 produced no significant change in forearm blood flow. After reinstitution of therapy, B9340 again resulted in vasoconstriction (PϽ0.03). 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 B 1 receptor.

Bradykinin Improves Left Ventricular Diastolic Function Under Long-Term Angiotensin-Converting Enzyme Inhibition in Heart Failure

“…In patients with CHF who received long-term ACEI therapy, a B 2 receptor antagonist had no discernible vasoconstrictive effects on forearm blood flow; 22 conversely, a combined B 1 and B 2 receptor antagonist produced vasoconstriction. 23 In the present study, we did not verify the role of B 1 receptors in the vasculature; however, in our tachycardia-induced CHF model, which is quite similar to the clinical findings of the dilated cardiomyopathy seen in humans, endogenous BK did not appear to participate in arterial blood pressure regulation, at least via a B 2 receptor.…”

Contribution of Leu and Hyp residues to antioxidant and ACE-inhibitory activities of peptide sequences isolated from squid gelatin hydrolysate

“…Angiotensin-I converting enzyme (ACE) plays an important role in the regulation of blood pressure and hypertension because catalyzes the conversion of inactive angiotensin-I into angiotensin-II, a potent vasoconstrictor (Goodfriend, Elliott & Catt, 1996) and inactivates bradykinin, a potent vasodilator (Witherow, Helmy, Webb, Fox & Newby, 2001). Synthetic inhibitors of ACE are often used to treat hypertension (Pahor, Psaty, Alderman, Applegate, Williamson & Furberg, 2000) and other cardio-related diseases.…”

Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium-Mediated Vasodilation in Conscious Dogs

“…3,4 In patients with HF chronically treated by ACE inhibitors, BK receptor blockade with a mixed B1 and B2 receptor antagonist produces a dosedependent vasoconstriction that disappears after withdrawal of ACE inhibitor therapy, suggesting a role of BK at the vascular level in the chronic treatment with these drugs. 5 In the coronary circulation, previous studies have shown that BK participates in the regulation of coronary vascular tone 6 and improvement of coronary endothelial dysfunction and coronary flow reserve by ACE inhibitors. 7,8 Recent studies have demonstrated that, in contrast with the impaired vasodilator response to acetylcholine usually observed in HF, 9 -11 the vasodilator effect of exogenous BK is preserved in pacing-induced HF in dogs 4 and that endogenous BK plays a significant role in the vasomotor control in HF.…”