Probucol promotes functional reendothelialization in balloon-injured rabbit aortas.
BACKGROUND
Probucol remains the only conventional drug that reduces restenosis after coronary angioplasty. Apart from its weak cholesterol-lowering effect, probucol has antioxidant properties, but it remains unclear how this drug inhibits restenosis.


RESULTS
Aortic balloon-injured New Zealand White rabbits were fed 2% (wt/wt) cholesterol-enriched or normal chow, with 0.75% (wt/wt) probucol (P) or without (controls, C) for 6 weeks. Endothelial denudation of the abdominal aorta was performed at week 3 with a 3F Fogarty embolectomy catheter. The arteries were harvested after week 6 and analyzed for histology, lipids and antioxidants, and endothelial regeneration and function. Probucol significantly decreased aortic intima-to-media ratio (cholesterol-fed: C, 1.10+/-0.08 versus P, 0.70+/-0.10; normal: C, 0.89+/-0.02 versus P, 0.83+/-0.05; P<0.05) and the numbers of proliferating intimal smooth muscle cells and lowered serum cholesterol without altering the proportion of aortic lipids that was oxidized. Probucol promoted endothelial regeneration in the injured aorta in cholesterol-fed rabbits (25% increase in reendothelialization, P<0.05) and in those on normal chow (37% increase, P<0.01). This was associated with both improved endothelial function as assessed by enhanced aortic ring relaxation and cGMP production in response to acetylcholine and decreased intimal thickening.


CONCLUSIONS
Probucol inhibits intimal thickening in balloon-damaged arteries of rabbits by promoting the regeneration of functional endothelium, without affecting the proportion of aortic lipids that was oxidized. This novel in vivo finding helps explain how probucol inhibits restenosis after coronary angioplasty and highlights potential new targets for therapeutic intervention.
Lau
Antony K
AK
The Heart Research Institute, Sydney, Australia.
Leichtweis
Steven B
SB
Hume
Peter
P
Mashima
Ryuichi
R
Hou
Jing Y
JY
Chaufour
Xavier
X
Wilkinson
Barbara
B
Hunt
Nicholas H
NH
Celermajer
David S
DS
Stocker
Roland
R
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000293:injuries / Q000473:pathology / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000517:prevention & control; D066298:In Vitro Techniques; D050356:Lipid Metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D011341:Probucol / Q000494:pharmacology*; D011817:Rabbits; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D017540:Tunica Media / Q000187:drug effects / Q000473:pathology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D000975:Antioxidants; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D011341:Probucol