Potential importance of tissue angiotensin-converting enzyme inhibition in preventing neointima formation.
BACKGROUND
Angiotensin II (Ang II) induces vascular smooth muscle cell migration and growth in vitro and induces DNA synthesis in vascular smooth muscle in vivo. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists inhibit neointimal hyperplasia in many experimental models of restenosis. However, recent clinical trials (MERCATOR and MARCATOR) reported that treatment with low (antihypertensive) doses of an ACE inhibitor (cilazapril) failed to prevent restenosis. Because ACE activity is induced in the neointima after injury, we hypothesize that the inhibition of neointimal development may be dependent on the suppression of tissue ACE activity, which in turn is dependent on the dose of the ACE inhibitor.


RESULTS
To test this hypothesis, we treated rats with increasing doses of an ACE inhibitor, quinapril, before injury of the carotid artery. Blood pressure, serum and tissue ACE activity, and neointimal area were measured. The results demonstrated a dose-dependent inhibition by quinapril of serum and tissue ACE activities and neointima formation. However, the IC50s for blood pressure reduction and serum ACE inhibition were significantly lower than that observed for the suppression of neointima formation. The degree of neointimal formation showed a better correlation with residual tissue ACE than with serum ACE or blood pressure.


CONCLUSIONS
These results demonstrate a dissociation of the ability of an ACE inhibitor to decrease blood pressure and inhibit circulating ACE activity from its ability to inhibit tissue ACE activity. These results suggest that the need for a higher dose of an ACE inhibitor for the inhibition of neointima formation may be due to the relative difficulty in inhibiting tissue ACE activity.
Rakugi
H
H
Falk Cardiovascular Research Center, Division of Cardiovascular Medicine, Stanford University School of Medicine, Calif.
Wang
D S
DS
Dzau
V J
VJ
Pratt
R E
RE
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects; D020212:Carotid Artery Injuries; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D000077583:Quinapril; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines; D017539:Tunica Intima / Q000187:drug effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077583:Quinapril