Pharmacological and mechanistic aspects concerning the use of heparin and β‐cyclodextrin tetradecasulfate for the treatment of vascular restenosis

Aberrant smooth muscle cell (SMC) growth within the intimal tissues of the arterial wall plays a major role in the development of restenosis which commonly occurs following coronary bolloon angioplasty. Studies from several laboratories have demonstrated that heparin reduced neointimal formation in response to balloon denudation in vivo and that heparin also inhibits the growth and migration of cultured SMC in vitro. In this paper, data will be presented demonstrating that heparin markedly inhibits neointimal thickening and bromodexyuridine incorporation into newly synthesized DNA in a fully characterized rat model of arterial injury. Heparin treatment begun at the time of angioplasty and continued for as little as 2–4 days resulted in substantial inhibiton of neointimal formation 14 days later. The relevance of the rat model to human restenosis and the positive and negative aspects concerning the use of heparin and heparin‐like molecules for the treatment of vascular restenosis will be discussed. In addition, we will show that heparin recognizes specific binding sites on the surface of cultured aortic SMC which is a feature possibly associated with the anti‐proliferative mechanism of action of heparin. Finally, a highly sulfated cyclic polysaccharide, β‐cyclodextrin tetradecasulfate (S‐β‐CD), was found to significantly inhibit neointimal formation in the rat model of arterial injury. S‐β‐CD retains several positive aspects but lacks some of the negative features associated with the chronic use of heparin for the treatment of vascular restenosis.