title: Long-term treatment with nifedipine suppresses coronary hyperconstricting responses and inflammatory changes induced by paclitaxel-eluting stent in pigs in vivo: possible involvement of Rho-kinase pathway.
abstract: OBJECTIVE
  Accumulating evidence indicates that coronary vasoconstricting responses are enhanced at the edges of coronary segment implanted with a drug-eluting stent (DES) compared with a bare-metal stent (BMS) in humans. We have recently demonstrated that Rho-kinase pathway plays an important role in DES-induced coronary hyperconstricting responses associated with inflammatory changes in pigs in vivo. This study examined whether long-term treatment with calcium channel blocker suppresses DES-induced coronary hyperconstricting responses in pigs in vivo.
  
  
  RESULTS
  Paclitaxel-eluting stent (PES) and a BMS were randomly implanted in the left coronary arteries in male domestic pigs with and without long-acting nifedipine (NIF, 4 mg/kg/day) for 4 weeks (n = 7 each). Coronary vasomotion was evaluated by quantitative coronary angiography at least 24 h after withdrawal of NIF to avoid its direct effects on coronary vasomotion. In the control group (without NIF), coronary vasoconstricting responses to serotonin (10 and 100 µg/kg, i.c.) were significantly enhanced at the PES site compared with the BMS site (P = 0.009), which were abolished by hydroxyfasudil (90 and 300 µg/kg, i.c.), a selective Rho-kinase inhibitor. The PES-induced vasoconstricting responses were significantly inhibited in the NIF group (P = 0.019). Histological examination showed that inflammatory cell accumulation and microthrombus formation were enhanced at the PES site compared with the BMS site (P < 0.05), both of which were significantly suppressed by NIF associated with reduced Rho-kinase expression and activity (P < 0.05).
  
  
  CONCLUSIONS
  These results indicate that long-term treatment with NIF suppresses PES-induced coronary abnormalities partly through Rho-kinase pathway inhibition in vivo.
authors.affiliation: Department of Cardiovascular Medicine,  Tohoku University Graduate School of Medicine, Seiryo-machi, Aoba-ku, Sendai 980-8574,  Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Tsuburaya
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yasuda
authors.forename: Takashi
authors.initials: T
authors.lastname: Shiroto
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Ito
authors.forename: Jun Yi
authors.initials: JY
authors.lastname: Gao
authors.forename: Kentaro
authors.initials: K
authors.lastname: Aizawa
authors.forename: Yoku
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: Kenta
authors.initials: K
authors.lastname: Ito
authors.forename: Jun
authors.initials: J
authors.lastname: Takahashi
authors.forename: Hatsue
authors.initials: H
authors.lastname: Ishibashi-Ueda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003331:Coronary Vessels; D054855:Drug-Eluting Stents; D007150:Immunohistochemistry; D008297:Male; D009543:Nifedipine / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D011897:Random Allocation; D015398:Signal Transduction; D034421:Sus scrofa; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D054460:rho-Associated Kinases; D009543:Nifedipine; D017239:Paclitaxel