Inhibition of kinin metabolism and the role of the vascular B₁ kinin receptor in patients with congestive heart failure

BACKGROUND Angiotensin-converting enzyme and neutral endopeptidase are endothelial metallopeptidases that metabolise bradykinin. Inhibitors of angiotensinconverting enzyme improve symptoms and survival in patients with heart failure and vascular disease and potentiate bradykinin-mediated vasodilatation and endothelial tissue plasminogen activator release. The vascular actions of kinins are mediated by an inducible B₁ receptor and a constitutively expressed B₂ receptor. Vascular B₁ kinin receptor expression is markedly upregulated with left ventricular dysfunction and angiotensin-converting enzyme inhibition, but its role in man remains unclear.OBJECTIVES The aims of this thesis were first, to confirm biological activity of kinin receptor agonists and antagonists in human vascular tissue in vitro: second, to determine the contribution of bradykinin to the systemic haemodynamic effects of angiotensin-converting enzyme inhibition in patients with heart failure: third, to determine the effects of neutral endopeptidase inhibition on the vascular actions of bradykinin in patients treated with angiotensin-converting enzyme inhibition: fourth and finally, to determine the contribution of the B₁ kinin receptor to the vascular actions of kinins in patients with heart failureMETHODS Myography The vasomotor effects of kinin peptides were determined using myography of human umbilical vein rings. Heart failure: Systemic circulation After 6 weeks of enalapril or losartan therapy, patients underwent right heart catheterisation and received an intravenous infusion of the bradykinin receptor antagonist, B9340. Systemic haemodynamic variables were recorded. Peripheral circulation Blood flow and plasma fibrinolytic parameters were determined in both forearms using venous occlusion plethysmography and venous blood sampling. Drugs were administered via the brachial artery of the non-dominant forearm. The effect of the neutral endopeptidase inhibitor, thiorphan, on the vascular actions of bradykinin was examined in patients maintained on angiotensin-converting enzyme inhibition. Vascular Bi receptor function was examined using selective peptidic kinin receptor agonists and antagonists.RESULTS Biological activity of kinin receptor agonists and antagonists was confirmed in human umbilical vein. Systemic bradykinin antagonism caused an increase in mean arterial pressure and systemic vascular resistance and attenuated the fall in pulmonary arterial and pulmonary arterial wedge pressures in patients treated with enalapril compared to losartan. Compared to placebo, thiorphan augmented the vasomotor and fibrinolytic actions of bradykinin in patients treated with chronic angiotensin-converting enzyme inhibition. Bi receptor agonism and antagonism had no effect on vascular tone or enothelial tissue plasminogen activator release in the presence or absence of angiotensin-converting enzyme inhibition. The B2 receptor agonist, bradykinin, caused vasodilatation and tissue plasminogen activator release and these effects were markedly augmented by angiotensin-converting enzyme inhibition.CONCLUSIONS Bradykinin contributes to the systemic haemodynamic effects of longterm angiotensin-converting enzyme inhibition in patients with heart failure. Neutral endopeptidase contributes to the metabolism of bradykinin in patients with heart failure maintained on angiotensin-converting enzyme inhibitor therapy. Our findings may explain some of the apparent clinical differences between angiotensinconverting enzyme inhibitors and angiotensin receptor blockers, as well as the greater vasodepressor effect observed with combined angiotensin-converting enzyme and neutral endopeptidase inhibition when compared to angiotensin-converting enzyme inhibition alone. Finally, the B₁ kinin receptor does not appear to have a major vasomotor or fibrinolytic role in patients with heart failure. Augmentation of kinin-mediated vasodilatation and tissue plasminogen activator release by angiotensin-converting enzyme inhibition is restricted to the B₂ recepto