FK409, a new nitric-oxide donor, suppresses smooth muscle proliferation in the rat model of balloon angioplasty.
The effect of FK409, a new nitric-oxide (NO) donor, on neointimal formation of rat carotid arteries following balloon injury was studied. The intimal thickening at 14 days was strongly suppressed by twice daily administration of FK409 at 10 mg/kg from 2 days before to 13 days after injury. The neointima area and neointima/media ratio were decreased by 48.0% (P < 0.01) and 38.5% (P < 0.01), respectively, compared with control. On the other hand, isosorbide dinitrate (ISDN), a classical nitro-vasodilator, did not suppress intimal thickening even at 100 mg/kg twice a day. An in vivo 5-bromo-2'-dedoxyuridine (BrdU) uptake study revealed that FK409 inhibited the proliferative response of smooth muscle cells (SMC) in media at early stage of injury. In fact, the neointimal formation at 14 days was inhibited by the short term administration of FK409 only from the day of injury to 4 days after at 10 mg/kg twice a day. In cultured rat SMC, FK409 (1-10 mumol/l) markedly enhanced intracellular c-GMP and inhibited the proliferation in 10% FBS-containing medium. These results suggest that FK409 suppresses intimal thickening following balloon injury of the rat carotid artery by inhibition of SMC proliferation.
Department of Pharmacology, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan.
J
J
Seki
M
M
Nishio
Y
Y
Kato
Y
Y
Motoyama
K
K
Yoshida
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects* / Q000473:pathology; D020212:Carotid Artery Injuries; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D009574:Nitro Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D014665:Vasodilator Agents / Q000494:pharmacology*
D009574:Nitro Compounds; D014665:Vasodilator Agents; D009569:Nitric Oxide; C061872:FK 409; D001973:Bromodeoxyuridine; D006152:Cyclic GMP; D007548:Isosorbide Dinitrate