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 angio plasty. Its utility in this setting is limited by the inability to use high doses (secondary to anticoagulant effects) and the need for subc utaneous administration. We tested the ability of beta-cyclodextrin te tradecasulfate (CDT), a nonanticoagulant synthetic heparin mimic, to i nhibit smooth muscle cell proliferation in vitro and tested its effica cy when orally administered for the prevention of angioplasty restenos is in a rabbit atherosclerosis model. Vascular smooth muscle cells wer e cultured from rabbit aortas by the explant technique. Passaged cells were plated at low density in microtiter plates in the presence or ab sence of varying concentrations of heparin or CDT in culture medium co ntaining 10% fetal calf serum. Using both H-3-thymidine incorporation and total protein assays, both heparin and CDT caused a similar dose-d ependent inhibition of proliferation. We next tested the effect of ora lly administered CDT in the prevention of restenosis in focal femoral artery arteriosclerotic lesions created in hypercholesterolemic New Ze aland White rabbits by air-dessication endothelial injury and subseque nt peripheral angioplasty. Animals were followed up for 1 month and we re fed normal chow supplemented by tap water with or without CDT. In a nimals receiving the highest concentration of CDT (2 mg/mL drinking wa ter), the percentage of arterial cross-sectional area with intimal hyp erplasia 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 mea sured 1 month after angioplasty was reduced more in control than in CD T animals (-22% versus -2%, p<0.05). The restenosis rate (defined as l oss of greater-than-or-equal-to 50% of the initial pin) was 75% in con trol animals and 25% in animals receiving CDT (p<0.05). We conclude th at the heparin mimic CDT inhibits smooth muscle cell proliferation in vitro and that its oral administration reduces both intimal hyperplasi a and angiographic evidence of restenosis in this rabbit model of angi oplasty.