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 primary events that govern neointimal thickening and thus they determine the extent to which delayed restenosis occurs after percutaneous transluminal coronary angioplasty. In this study, the in vitro and in vivo smooth muscle cell antichemotactic and antiproliferative properties of a 2-aminochromone, 2-(4-morpholinyl)-8-(3-pyridinylmethoxy)-4H-1-benzopyran-4-one (U-86983), were examined. Migration and proliferation of early-passage rat vascular smooth muscle cells were inhibited by U-86983 in a concentration-dependent manner (IC50S, approximately 10 microM and 3.5 microM, respectively). Longer-term studies showed that the proliferation of smooth muscle cells was inhibited by U-86983 for at least 7 days and was fully reversible on removal of the drug. In addition, the effect of U-86983 on neointimal formation was examined in rats subjected to left common carotid artery balloon dilatation injury. Continual (2-week) i.v. administration of U-86983 (216 mg kg-1 day-1) resulted in a mean plasma drug concentration of 2.39 micrograms/ml (blood level, approximately 3.5 microM) and a 42% (P = .003) reduction in the neointima/media ratio of the injured artery. In agreement with the in vitro reversibility results, administration of U-86983 for only 2, 4 or 7 days did not affect significantly the neointimal thickness measured at 14 days, which indicated that the stimuli for smooth muscle cell migration and/or proliferation were still present 1 week after injury.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Medicinal Chemistry, Upjohn Laboratories, Kalamazoo, Michigan.
L A
LA
Erickson
P D
PD
Bonin
D G
DG
Wishka
J
J
Morris
R J
RJ
Dalga
D J
DJ
Williams
G J
GJ
Wilson
J L
JL
Hoover
C A
CA
Simmons
S J
SJ
Humphrey
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002867:Chromones; D009025:Morpholines; C090113:U 86983