Bradykinin-mediated cardiovascular protective actions of ACE inhibitors. A new dimension in anti-ischaemic therapy?

In addition to being accepted therapy in hypertension and heart failure, ACE inhibitors may well offer a new dimension in anti-ischaemic therapy. Currently, anti-ischaemic properties have been demonstrated by ACE inhibitors in selected patient groups, including patients with left ventricular dysfunction with or without a direct temporal relationship with myocardial infarction. Anti-ischaemic effects of ACE inhibitors become apparent late after initiation of treatment and suggest a structural rather than a functional effect. Underlying mechanisms may include a reduction in ventricular dilatation and (abnormal) cardiac hypertrophy, leading to less myocardial oxygen demand and, possibly, improved subendocardial blood supply, and vasculoprotective effects, i.e. anti-atherosclerotic and antiremodelling properties, a beneficial effect on the fibrinolytic system and an improvement in abnormal endothelial vasodilator function. The latter aspect is most probably the pivotal mode of action where the anti-ischaemic profile of ACE inhibition is concerned. An improvement in endothelial dysfunction has been shown in patients with mild to moderate coronary artery disease [Trial on Reversing ENdothelial Dysfunction (TREND)]. It is of importance that, in both clinical experiments and human studies, the role of bradykinin appears central in the structural and functional cardiovascular effects of ACE inhibition. This is particularly true for the improvement of impaired endothelial function. Myocardial ischaemia evokes vasoconstrictor neurohormonal activation, which may lead to coronary vasoconstriction in diseased coronary segments. The subsequent abnormal endothelial function leads to diminished coronary flow and also increases systemic vasotone and afterload, thus unfavourably altering the myocardial oxygen supply/demand ratio. Under laboratory conditions, acute ACE inhibition counteracts this activation in humans. However, it is speculated that this anti-ischaemic mechanism may become operative and clinically important during long term oral ACE inhibitor therapy when endothelial function improves, and may subsequently protect against the vasoconstrictor effect of neurohormonal activation. As it is unlikely that the mechanisms mentioned above are only relevant in patients with ventricular dysfunction or heart failure, several large controlled trials are currently examining the long term anti-ischaemic and cardiovascular protective effects of ACE inhibition in patients at risk of a cardiovascular event [Heart Outcomes Prevention Evaluation study (HOPE)], with a normal cardiac function [Prevention of Events with ACE inhibition study (PEACE)] or in all patients with coronary artery disease irrespective of cardiac function [EUropean trial of Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA)].