INHIBITION OF SMOOTH-MUSCLE CELL-PROLIFERATION AND NEOINTIMAL GROWTH BY LOW-ANTICOAGULANT HEPARIN

Low-anticoagulant heparin (LA-heparin) obtained by affinity chromatogr aphy on antithrombin III Sepharose inhibits the poliferation of cultur ed arterial smooth muscle cells in an in vitro bioassay system as effe ctively as standard heparin. A growth inhibition of smooth muscle cell s of about 60% is achieved when LA-heparin or heparin is added to the culture medium to a concentration of 50 mu g/ml. In normolipemic rats LA-heparin suppresses the formation of neointimal thickenings and sten osis after balloon catheter-induced deendothelialization of the caroti d artery. In terms of mass a dose of 5 mg/kg body weight/d given subcu taneously twice daily one week before and 2 weeks after balloon injury the cross sectional area of the neointima is reduced to 36% as compar ed with the nontreated control group (100%). This 64% reduction is sta tistically highly, significant (p < 0.001). After treatment with 0.5 m g LA-heparin/kg/d the reduction of the neointima was 11% (p < 0.05). A t a dose of 5 mg/kg body weight single or repeated administrations of LA-heparin caused only a small and transient increase in activated par tial thromboplastin time values. The results show that subcutaneous ad ministration of LA-heparin very effectively prevents smooth muscle cel l proliferation and balloon catheter-induced neointimal growth. The we ll tolerated systemic application of this chemically non-modified LA-h eparin might justify clinical trials for prevention of restenosis afte r percutaneous transluminal coronary angioplasty or other invasive car diovascular interventions without complications of bleeding.