ACE-INHIBITION VERSUS ANGIOTENSIN-II, AT1 RECEPTOR ANTAGONISM - A REVIEW OF EFFECTS ON INTIMAL LESION FORMATION IN ANIMAL-MODELS OF VASCULAR INJURY, RESTENOSIS, AND ATHEROSCLEROSIS

We recently demonstrated that the angiotensin converting enzyme inhibi tor (ACEi) benazepril reduced balloon-induced lesion formation solely by inhibiting smooth muscle cell (SMC) migration, whereas the Ang II,A T1 antagonist losartan reduced lesion formation by inhibiting both SMC migration and proliferation [Prescott et al. (1991): Am J Pathol 139: 1291-1296.]. We thus proposed that in order for both SMC migration and proliferation to be reduced by ACEi treatment, a dose must be selecte d which is greater than the dose necessary to reduce blood pressure. R ecent evidence that ACEi prevention of early intimal lesion formation following balloon injury can be reversed by simultaneous administratio n of the bradykinin antagonist, Hoe 140 [de-Blois et al. (1992): Circu lation 86 [Suppl I]:I-226.] raises the possibility that low doses of A CEi treatment may be sufficient to inhibit lesion formation via mechan isms independent of effects on Ang II production but that high doses o f ACEi treatment are necessary to prevent the local formation of Ang I I. The present review therefore analyzes the results of ACEi treatment on lesion formation following balloon catheterization, vascular stent ing, or angioplasty. Effects on lesion formation are correlated with t he importance of SMC migration vs. proliferation in the specific model employed. In addition, we present evidence to support our speculation that ACEi reduction of both atherosclerosis and restenotic lesions in the hypercholesterolemic rabbit is primarily due to inhibition of mon ocyte emigration into the vessel wall and is independent of effects on SMC migration or proliferation. Finally, we present preliminary resul ts from our efforts to develop a rabbit angioplasty model in which mac rophage-derived foam cells are not the primary component of either the initial ''atherosclerotic'' lesion or the restenotic lesion post-angi oplasty.