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

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. 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 g/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 g/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). These results indicate that long-term treatment with NIF suppresses PES-induced coronary abnormalities partly through Rho-kinase pathway inhibition in vivo.