Role of Bradykinin in the Vasodilator Effects of Losartan and Enalapril in Patients With Heart Failure

Abstract

Background-ACE inhibitors have been shown to potentiate the effects of exogenous bradykinin by inhibition of its breakdown. Despite this, there is little evidence that inhibition of endogenous bradykinin breakdown actually contributes to the effects of ACE inhibitors, or indeed, other inhibitors of the renin-angiotensin system, such as angiotensin II type I receptor (AT 1 ) antagonists, and no evidence at all that it does so in patients with heart failure. Methods and Results-Twelve patients with heart failure (11 male, 1 female, ages 59 to 81 years) were randomized to double-blind crossover treatment with enalapril 10 mg BID followed by losartan 25 mg BID, or the reverse, each for 5 weeks. At the end of each treatment period, forearm blood flow was measured by venous occlusion plethysmography during an intrabrachial infusion of bradykinin before and after an intrabrachial infusion of Hoe-140 (a potent, selective, and long-acting bradykinin antagonist). Bradykinin caused profound vasodilatation after enalapril (peak, 357Ϯ67%) and less after losartan (peak, 230Ϯ46%). Despite this, Hoe-140 had no discernible effects after enalapril or losartan. Similarly, this was despite the finding that Hoe-140 significantly reduced vasodilatation to bradykinin after enalapril (peak, 192Ϯ35%) and losartan (peak, 66Ϯ13%). Conclusions-Inhibition of endogenous bradykinin breakdown does not appear to contribute to the effects of ACE inhibition or AT 1 antagonism in the forearm of patients with heart failure at rest, despite the very obvious effects of ACE inhibition compared with AT 1 antagonism on exogenous bradykinin. (Circulation. 1999;100:268-273.)

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

“…26 The apparent disparity between our study and that by Davie et al 26 may reflect the differing pharmacological actions of HOE-140 and B9340. To address this issue, we subsequently assessed the effects of HOE-140 in a limited number of patients, including 4 subjects who had received B9340.…”

Angiotensin-Converting Enzyme Inhibition Increases Human Vascular Tissue-Type Plasminogen Activator Release Through Endogenous Bradykinin

“…15 The study confirms prior studies with HOE 140 indicating that endogenous BK does not contribute to resting vascular tone. 12,19,21 However, this is the first study to demonstrate that ACE inhibition increases constitutive forearm endothelial t-PA release through an effect on endogenous BK.…”

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

“…In the present study, the combination of FR and enalapril did not alter the systemic blood pressure and systemic vascular resistance compared with that of enalapril alone. 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.…”