title: Model system to study interaction of platelets with damaged arterial wall. II. Inhibition of smooth muscle cell proliferation by dipyridamole and AH-P719.
abstract: A new in vivo model for the initial events in atherogenesis was employed to investigate drugs which may inhibit intimal muscle cell proliferation following repeated limited endothelial cell injury. An artery forceps was placed over the central artery of the ear of an anesthetized rabbit for 30 min. The forceps were removed, blood flow resumed in the vessel, and platelets contacted the damaged vessel wall. When a vessel was injured two or more times the smooth muscle cells of the media migrated into the intima and proliferated there between 1 and 3 weeks after the last injury despite restoration of an apparently intact endothelium. The intima of control undamaged vessels sometimes contained a few individual smooth muscle cells while vessels injured two, four, or six times showed correspondingly increasing numbers of layers of intimal smooth muscle cells covering increasing amounts of the intima. Arteries from thrombocytopenic rabbits showed, at most, a single layer of smooth muscle cells covering a small area. In rabbits pretreated with dipyridamole (1.5 mg/kg) for 3 days before each injury, proliferation was also limited to a small area. Neither aspirin (8 mg/kg) nor ticlopidine (40 mg/kg, 5X over 3 days), which inhibit platelet aggregation ex vivo, nor the continuous presence of heparin (800 U/kg, bid), reported to inhibit smooth muscle cell growth in vitro and in vivo, prevented smooth muscle cell proliferation in response to two injuries. However, a potent inhibitor of platelet cyclic-adenosine monophosphate (cAMP) phosphodiesterase, AH-P719 (1.5 or 2.1 mg/kg), was able to inhibit intimal smooth muscle cell proliferation in doses that inhibited platelet aggregation ex vivo.
authors.affiliation: Cardeza Foundation, Department of Medicine, Philadelphia, Pennsylvania 19107.
authors.forename: C M
authors.initials: CM
authors.lastname: Ingerman-Wojenski
authors.forename: M J
authors.initials: MJ
authors.lastname: Silver
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D001161:Arteriosclerosis / Q000473:pathology* / Q000503:physiopathology; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D004176:Dipyridamole / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D006493:Heparin / Q000494:pharmacology; D007093:Imidazoles; D008297:Male; D008855:Microscopy, Electron, Scanning; D008955:Models, Cardiovascular; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D011817:Rabbits
chemical_list: D007093:Imidazoles; C049655:4-(2-(1-imidazolyl)ethoxy)benzoic acid; D004176:Dipyridamole; D006493:Heparin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D001241:Aspirin