IN-VITRO AND IN-VIVO INHIBITION OF RAT VASCULAR SMOOTH-MUSCLE CELL-MIGRATION AND PROLIFERATION BY A 2-AMINOCHROMONE U-86983

Vascular smooth muscle cell migration and proliferation are the primar y events that govern neointimal thickening and thus they determine the extent to which delayed restenosis occurs after percutaneous translum inal coronary angioplasty. In this study, the in vitro and in vivo smo oth muscle cell antichemotactic and antiproliferative properties of a 2-aminochromone, inyl)-8-(3-pyridinylmethoxy)-4H-1-benzopyran-4-one (U -86983), were examined. Migration and proliferation of early-passage r at vascular smooth muscle cells were inhibited by U-86983 in a concent ration-dependent manner (IC(50)s, similar to 10 mu M and 3.5 mu M, res pectively). Longer-term studies showed that the proliferation of smoot h muscle cells was inhibited by U-86983 for at least 7 days and was fu lly reversible on removal of the drug. in addition, the effect of U-86 983 on neointimal formation was examined in rats subjected to left com mon carotid artery balloon dilatation injury. Continual (2-week) i.v. administration of U-86983 (216 mg kg(-1) day(-1)) resulted in a mean p lasma drug concentration of 2.39 mu g/ml (blood level, similar to 3.5 mu M) and a 42% (P = .003) reduction in the neointima/media ratio of t he injured artery. In agreement with the in vitro reversibility result s, administration of U-86983 for only 2, 4 or 7 days did not affect si gnificantly the neointimal thickness measured at 14 days, which indica ted that the stimuli for smooth muscle cell migration and/or prolifera tion were still present 1 week after injury. Taken together, these res ults show that U-86983 represents a class of compounds that may be use ful in the study of the cellular proliferative processes that underlie hyperplastic disorders, such as delayed restenosis.