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
Mf. Prescott et Wk. Sawyer, 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, Drug development research, 29(2), 1993, pp. 88-93
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.