Suppression of arterial intimal hyperplasia by cilostamide, a cyclic nucleotide phosphodiesterase 3 inhibitor, in a rat balloon double-injury model.
The effects of cilostamide, a cyclic nucleotide phosphodiesterase 3 (PDE3) selective inhibitor, on vascular intimal hyperplasia were evaluated using a single-balloon injury model and a double-injury model in which the rat common carotid artery was subjected to a second injury at a site injured 14 days previously. In the double-injury model, the second balloon injury caused more severe intimal hyperplasia (intima/media (IM) ratio, 1.88+/-0.10) than in the single-injury model (1.09+/-0.08). Histopathological study revealed that vascular smooth muscle cells (VSMC) were the predominant cell-type in the affected neointimal area. Oral administration of cilostamide for 2 weeks after the second injury suppressed intimal hyperplasia in the double-injury model (30 mg kg(-1) bid, 83% inhibition in terms of the IM ratio, P<0.05; 100 mg kg(-1) bid, 69% inhibition, P<0.05). Similar effects were also observed in the single-injury model with oral administration of cilostamide for 2 weeks (100 mg kg(-1) bid, 36% inhibition, P<0.01). Cilostamide inhibited DNA synthesis of cultured VSMC stimulated by foetal calf serum or different kinds of growth factors, but did not affect their migration stimulated by platelet-derived growth factor (PDGF)-BB. Cilostamide significantly increased the cyclic AMP concentration of VSMC dose-dependently. These results indicate that cilostamide suppresses intimal hyperplasia both in the single- and double-injury models of rat, presumably by inhibiting proliferation rather than migration of VSMC. It is suggested that PDE3 inhibitors might find application in preventing intimal hyperplasia following angioplasty such as percutaneous transluminal coronary angioplasty (PTCA) or stent.
Inoue
Y
Y
Thrombosis and Vascular Research Laboratory, Otsuka Pharmaceutical Co., Ltd. 463-10 Kagasuno, Kawauchi-cho, Tokushima, 771-0192, Japan.
Toga
K
K
Sudo
T
T
Tachibana
K
K
Tochizawa
S
S
Kimura
Y
Y
Yoshida
Y
Y
Hidaka
H
H
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D002404:Catheterization; D002452:Cell Count / Q000187:drug effects; D002478:Cells, Cultured; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004195:Disease Models, Animal; D006965:Hyperplasia / Q000188:drug therapy / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D015363:Quinolones / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects / Q000293:injuries / Q000473:pathology*
D010726:Phosphodiesterase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D015363:Quinolones; C021294:cilostamide; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3