INHIBITION OF SMOOTH-MUSCLE CELL-PROLIFERATION AND EXPERIMENTAL ANGIOPLASTY RESTENOSIS BY BETA-CYCLODEXTRIN TETRADECASULFATE

Heparin inhibits smooth muscle cell proliferation in vitro, a property that makes it potentially useful in preventing restenosis after angioplasty. Its utility in this setting is limited by the inability to use high doses (secondary to anticoagulant effects) and the need for subcutaneous administration. We tested the ability of beta-cyclodextrin tetradecasulfate (CDT), a nonanticoagulant synthetic heparin mimic, to inhibit smooth muscle cell proliferation in vitro and tested its efficacy when orally administered for the prevention of angioplasty restenosis in a rabbit atherosclerosis model. Vascular smooth muscle cells were cultured from rabbit aortas by the explant technique. Passaged cells were plated at low density in microtiter plates in the presence or absence of varying concentrations of heparin or CDT in culture medium containing 10% fetal calf serum. Using both H-3-thymidine incorporation and total protein assays, both heparin and CDT caused a similar dose-dependent inhibition of proliferation. We next tested the effect of orally administered CDT in the prevention of restenosis in focal femoral artery arteriosclerotic lesions created in hypercholesterolemic New Zealand White rabbits by air-dessication endothelial injury and subsequent peripheral angioplasty. Animals were followed up for 1 month and were fed normal chow supplemented by tap water with or without CDT. In animals receiving the highest concentration of CDT (2 mg/mL drinking water), the percentage of arterial cross-sectional area with intimal hyperplasia decreased from 50.5+/-1.7% (control) to 26.9+/-2.2% (p<0.001), with the intimal/medial ratio being decreased from 1.4+/-0.4 to 0.5+/-0.2 (p=0.056). Angiographically, the mean minimum lumen diameter measured 1 month after angioplasty was reduced more in control than in CDT animals (-22% versus -2%, p<0.05). The restenosis rate (defined as loss of greater-than-or-equal-to 50% of the initial pin) was 75% in control animals and 25% in animals receiving CDT (p<0.05). We conclude that the heparin mimic CDT inhibits smooth muscle cell proliferation in vitro and that its oral administration reduces both intimal hyperplasia and angiographic evidence of restenosis in this rabbit model of angioplasty.