Inhibition of smooth muscle cell proliferation and neointimal growth by low-anticoagulant heparin.
Low-anticoagulant heparin (LA-heparin) obtained by affinity chromatography on antithrombin III Sepharose inhibits the proliferation of cultured arterial smooth muscle cells in an in vitro bioassay system as effectively as standard heparin. A growth inhibition of smooth muscle cells of about 60% is achieved when LA-heparin or heparin is added to the culture medium to a concentration of 50 micrograms/ml. In normolipemic rats LA-heparin suppresses the formation of neointimal thickenings and stenosis after balloon catheter-induced deendothelialization of the carotid artery. In terms of mass a dose of 5 mg/kg body weight/d given subcutaneously twice daily one week before and 2 weeks after balloon injury the cross sectional area of the neointima is reduced to 36% as compared with the nontreated control group (100%). This 64% reduction is statistically highly significant (p < 0.001). After treatment with 0.5 mg LA-heparin/kg/d the reduction of the neointima was 11% (p < 0.05). At a dose of 5 mg/kg body weight single or repeated administrations of LA-heparin caused only a small and transient increase in activated partial thromboplastin time values. The results show that subcutaneous administration of LA-heparin very effectively prevents smooth muscle cell proliferation and balloon catheter-induced neointimal growth. The well tolerated systemic application of this chemically non-modified LA-heparin might justify clinical trials for prevention of restenosis after percutaneous transluminal coronary angioplasty or other invasive cardiovascular interventions without complications of bleeding.
Völker
W
W
Institute for Arteriosclerosis Research, University of Münster, Münster/Westf, Germany.
Böhm
A
A
Schmidt
A
A
Svahn
C M
CM
Gellerbring
A K
AK
Mattsson
C
C
Ekvärn
S
S
Robenek
H
H
Buddecke
E
E
D000800:Angioplasty, Balloon; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002339:Carotid Arteries / Q000166:cytology / Q000187:drug effects; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006493:Heparin / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000925:Anticoagulants; D006493:Heparin