Suppression of arterial intimal hyperplasia by cilostamide, a cyclic nucleotide phosphodiesterase 3 inhibitor, in a rat balloon double‐injury model

Abstract

1 The eects 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. 2 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 aected neointimal area. 3 Oral administration of cilostamide for 2 weeks after the second injury suppressed intimal hyperplasia in the double-injury model (30 mg kg 71 bid, 83% inhibition in terms of the IM ratio, P50.05; 100 mg kg 71 bid, 69% inhibition, P50.05). Similar eects were also observed in the singleinjury model with oral administration of cilostamide for 2 weeks (100 mg kg 71 bid, 36% inhibition, P50.01). 4 Cilostamide inhibited DNA synthesis of cultured VSMC stimulated by foetal calf serum or dierent kinds of growth factors, but did not aect their migration stimulated by platelet-derived growth factor (PDGF)-BB. Cilostamide signi®cantly increased the cyclic AMP concentration of VSMC dose-dependently. 5 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 ®nd application in preventing intimal hyperplasia following angioplasty such as percutaneous transluminal coronary angioplasty (PTCA) or stent.

The role of cyclic nucleotide phosphodiesterases in the regulation of adipocyte lipolysis

“…Synergistic effects of PDE3 and PDE4 inhibitors have been documented previously in several cell-or tissue-based functional assays, including relaxation of smooth muscle strips (41)(42)(43), attenuation of vascular smooth muscle cell proliferation (39,44), stimulation of vascular smooth muscle cell migration (45), induction of apoptosis in leukemic cells (44,46), attenuation of T-lymphocyte proliferation (47,48), and inhibition of T-lymphocyte interleukin-2 synthesis (47). In mice injected with T-cell mitogens, PDE3 and PDE4 inhibitors also act synergistically in vivo to attenuate systemic tumor necrosis factor-␣ release and protect against liver injury (49).…”

Role of Phosphodiesterase 3 in NO/cGMP-Mediated Antiinflammatory Effects in Vascular Smooth Muscle Cells

“…Inhibition of PDE3 has also been shown to mediate the inhibitory effect of NO in VSMC mitogenesis, 22 and the PDE3 inhibitor cilostamide suppressed arterial intimal hyperplasia in a rat balloon injury model. 29 Given that NO is an important antiatherogenic molecule in vivo, inhibition of PDE3 activity with PDE3-selective inhibitors may be an effective antiatherogenic strategy. It has already been shown that the PDE3 inhibitor cilostazol (an analogue of cilostamide) is an effective drug for the clinical treatment of symptoms of intermittent claudication due to peripheral arterial disease, which itself, is believed to be a manifestation of systemic atherosclerosis.…”

Reduced Phosphodiesterase 3 Activity and Phosphodiesterase 3A Level in Synthetic Vascular Smooth Muscle Cells: Implications for Use of Phosphodiesterase 3 Inhibitors in Cardiovascular Tissues

“…Recently, cilostazol, a structural analog of the PDE3 inhibitor used in our studies (cilostamide), has been considered a promising candidate drug for prevention of restenosis because of its vascular and platelet effects (Ochiai et al, 1999;Tanabe et al, 2001). Indeed, several studies have indicated some degree of success in suppressing neointimal formation in animal models using cilostazol (Inoue et al, 2000;Aoki et al, 2001). Results of trials in which both aspirin and cilostazol were delivered in combination after stenting showed results comparable to those obtained when aspirin and ticlopidine, an inhibitor of platelet aggregation, were used .…”