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.