Bradykinin - a contribution to blood pressure reduction with ACE inhibition in man?

Angiotensin II-converting enzyme (ACE) inhibitors have an established role in the treatment of hypertension and heart failure. These drugs not only pr event the conversion of angiotensin I to angiotensin II (AII) but, by inhib ition of kininase II, they modify the metabolism of several other vasoactiv e substances. There is good evidence that the inactivation of bradykinin (B K) is blocked by ACE inhibitors resulting in enhanced effects of circulatin g and tissue BK. There has been considerable controversy as to whether BK c ontributes to any of the beneficial or unwanted actions of ACE inhibitors. The availability of potent selective antagonists of bradykinin B-2, subtype receptors offers an experimental approach to explore the contribution of B K in man. The B2 receptor is responsible for the cardiovascular effects of BK in man. Icatibant acetate (HOE 140) has been used by ourselves and by ot hers in controlled trials in normotensive males on a normal salt intake in salt-depleted normotensives and hypertensives. In both studies, icatibant w as given by intravenous infusion with or without an ACE inhibitor. Both stu dies concluded that the BK antagonist significantly attenuated the acute fa ll in blood pressure after ACE inhibitor administration. Our study employed a double-blind design with ACE inhibition induced by int ravenous perindoprilat (active metabolite of perindopril). Combined B-2, an tagonism and ACE inhibition significantly reduced the mean maximum fall in blood pressure over the first 3 h after ACE inhibitor administration as wel l as the area under the blood pressure/time curve compared with ACE inhibit ion alone. Icatibant alone caused a small, but significant, increase in blo od pressure compared with placebo. In our study, coadministration did not i nfluence inhibition of plasma ACE or the reactive rise in active renin conc entration when compared with an ACE inhibitor alone. These studies in man suggest that at least part of the acute blood pressure lowering action of an ACE inhibitor is due to an interaction with bradykin in B-2, mechanisms. The results are consistent with experimental studies in vivo and with in vitro studies which implicate BK in endothelial function and vasodilatation by activation of nitric oxide and release of prostagland ins. The long-term importance of BK mechanisms in blood pressure reduction remains to be determined as do the implications of these findings to the be neficial effects of ACE inhibitors on outcome in patients with cardiovascul ar disease.