Differences in the effect of angiotensin-converting enzyme inhibitors on the rate of endothelial cell apoptosis: in vitro and in vivo studies.
OBJECTIVE
An imbalance between endothelial apoptosis and regeneration is one of the initiating events in atherosclerosis. Angiotensin-converting enzyme (ACE) inhibition corrects the endothelial dysfunction observed in coronary artery disease, and this could be the consequence of a reduction in the rate of endothelial apoptosis. The aim of this study was to investigate the effect of different ACE inhibitors on endothelial apoptosis.


METHODS
We examined the effect of five ACE inhibitors (enalapril, perindopril, quinapril, ramipril, and trandolapril) on the rate of endothelial apoptosis, either in vitro in human umbilical vein endothelial cells (HUVECs), using a serum deprivation method to induce apoptosis, or in vivo in rats, inducing apoptosis via endotoxic shock with Escherichia coli lipopolysaccharides (LPS).


RESULTS
We were unable to detect any significant effect of ACE inhibition on the rate of in vitro endothelial apoptosis at concentrations ranging from 5 x 10(-8) to 10(-6) M. In contrast, chronic in vivo administration of ACE inhibitors to rats at dosages that had similar hypotensive effects reduced the rate of LPS-induced apoptosis significantly for perindopril (P < 0.001) and nonsignificantly for the other ACE inhibitors. The order of potency of the ACE inhibitors tested was perindopril > ramipril >> quinapril = trandolapril = enalapril, with significant differences between perindopril and quinapril (P < 0.01), trandolapril (P < 0.001), and enalapril (P < 0.001). The difference between perindopril and ramipril did not reach significance.


CONCLUSIONS
Our experiments suggest differences between ACE inhibitors in terms of inhibition of endothelial apoptosis in vivo.
Ceconi
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C
Department of Cardiology, University of Ferrara, Corso Giovecca 203, 44100, Ferrara, Italy. claudio.ceconi@unife.it
Francolini
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G
Bastianon
D
D
Gitti
G L
GL
Comini
L
L
Ferrari
R
R
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013599:Systole / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D008070:Lipopolysaccharides; D009569:Nitric Oxide