Do ACE inhibitors modulate atherosclerosis?
The ACE/angiotensin II/bradykinin system is inextricably linked to some of the processes that contribute to the generation of atherosclerosis at genetic, molecular, biochemical and pharmacological levels. There is a large body of laboratory-derived experimental data that suggests that inhibition of ACE activity has antiproliferative, anti-inflammatory and vasodilatory effects that can modulate this atherosclerotic process from the earliest form of endothelial dysfunction, to delay of lesion formation in primary atherosclerosis or in myointimal proliferation after PTCA. The clinical evidence for these potential benefits is so far sparse. There are several possible explanations for these discrepancies. Firstly, the role of the ACE/bradykinin/angiotensin II system in the local vascular response to either the primary process of atherosclerosis, or to the injury induced by balloon angioplasty is likely to vary between species and models. Secondly, there is a tendency to ensure the presence of ACE inhibitor in high concentration before or during the vascular insult in animal models, whereas this has not been the case in the clinical studies of post-PTCA restenosis. Whilst the animal studies therefore offer potentially valuable insights into the mechanics of local vascular response, the ability of ACE inhibitors to interfere with such mechanisms now needs to be tested in clinical trials that are each aimed at precisely answering specific questions. The experimental data so far lend considerable support to the fact that drugs acting solely by interference with the angiotensin II-receptor complex are at a theoretical disadvantage, when compared with ACE inhibitors, since the former would be expected to have little effect on bradykinin-mediated activities. To the established benefits of ACE inhibitors in left ventricular dysfunction, and the interesting possibility that there may be an anti-ischaemic action in these circumstances, we may add the promise of the TREND study. In the coming years, there is an urgent requirement for intensive investigation into the ability of ACE inhibitors to modulate the various stages of the atherosclerotic spectrum. For now though, the jury remains out.
Curzen
N P
NP
Royal Brompton Hospital, London, U.K.
Fox
K M
KM
D015906:Angioplasty, Balloon, Coronary; D000804:Angiotensin II / Q000187:drug effects / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001920:Bradykinin / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D055502:Secondary Prevention
D000806:Angiotensin-Converting Enzyme Inhibitors; D000804:Angiotensin II; D001920:Bradykinin