Bradykinin contributes to the vascular actions of angiotensin-converting enzyme (ACE) inhibition via B₂ kinin receptor-mediated vasodilatation and endothelial tissue plasminogen activator (t-PA) release. Endothelial B₁ receptor expression is upregulated in the presence of cardiovascular disease and angiotensin-converting enzyme inhibition, but its function in man remains unknown. We have recently confirmed in vitro the efficacy of the selective peptidic agonist, Lys-des-Arg⁹-bradykinin, and antagonist, Lys-[Leu⁸]-des-Arg⁹-bradykinin, for the human vascular B₁ receptor. Using these pharmacological tools, we investigated the effects of B₁ receptor agonism and antagonism on vascular tone and t-PA release in vivo in patients with chronic heart failure treated with long-term ACE inhibition.

Eleven patients with heart failure were withdrawn from ACE inhibitor therapy for 2 weeks before receiving 6 weeks of treatment with enalapril (10 mg twice daily) and losartan (50 mg twice daily) in a randomized double-blind crossover trial. In the final week of each intervention, patients attended on two occasions and received an intra-brachial infusion of Lys-des-Arg⁹-bradykinin (1–10 nmol min^-1) and bradykinin (30–300 pmol min^-1) on one visit and Lys-[Leu⁸]-des-Arg⁹-bradykinin (1–10 nmol min^-1) and norepinephrine (60–540 pmol min^-1) on the other. Blood flow and plasma t-PA antigen were measured in both arms using venous occlusion plethysmography and venous blood sampling.

Bradykinin caused dose-dependent vasodilatation (forearm blood flow: + 450 ± 70% at bradykinin 300 pmol min^-1 during ACE inhibitor withdrawal) and norepinephrine caused dose-dependent vasoconstriction (forearm blood flow: – 40 ± 6% at norepinephrine 540 pmol min^-1 during ACE inhibitor withdrawal) in all studies ( p < 0.001 for all). There were no changes in blood flow with Lys-des-Arg⁹-bradykinin or Lys-[Leu⁸]-des-Arg⁹-bradykinin. Bradykinin caused a dose-dependent increase in t-PA antigen in the infused arm in all studies (t-PA antigen: 11.3 ± 1.4 ng ml^-1 at baseline, 16.3 ± 1.6 ng ml^-1 at bradykinin 300 pmol min^-1 during ACE inhibitor withdrawal, p < 0.001 for all). Compared with losartan therapy or ACE inhibitor withdrawal, enalapril augmented bradykinin-induced vasodilatation (blood flow: + 310 ± 60, + 453 ± 70 and +650 ± 100% at bradykinin 300 pmol min^-1 respectively, p < 0.005 and p < 0.05 respectively) and t-PA release approximately six fold ( p < 0.001 for both).