Abstract 4164: Rho-kinase Pathway Plays an Important Role in the Pathogenesis of Coronary Hyperconstricting Responses Induced by Drug-Eluting Stents in Pigs in vivo
Background: Recent clinical studies showed that coronary vasoconstricting responses are enhanced at the edge of coronary segment implanted with drug-eluting stent (DES). Since we have previously demonstrated the important role of Rho-kinase pathway in the molecular mechanism of coronary spasm in humans, we examined whether the pathway is also involved in the mechanism of coronary hyperconstricting responses induced by DES.
Methods and Results: In cultured human coronary VSMC, paclitaxel (1–1000 nM) concentration-dependently up-regulated Rho-kinase expression and increased Rho-kinase activity in vitro (n=6~9). In a porcine model, a paclitaxel-eluting stent (PES) and a bare-metal stent (BMS) were randomly implanted in the left coronary arteries. Four weeks after the implantation, coronary vasocon-stricting responses to serotonin (5-HT, 10 and 100 μg/kg, IC) were significantly enhanced at the PES site compared with the BMS site (45±4% vs. 30±3%, P<0.01), which were abolished by hydroxyfasudil (HF, 90 and 300 μg/kg, IC), a selective Rho-kinase inhibitor (Figure A⇓). Similar results were obtained with a sirolimus-eluting stent (SES) in vivo (Figure B⇓). PES enhanced inflammatory responses and microthrombus formation at the stent edge, where Rho-kinase expression and activity were increased. In organ chamber experiments, 5-HT-induced contractions of isolated coronary rings were significantly enhanced in the PES-edge site compared with the BMS-edge site (Figure C⇓).
Conclusions: These results indicate that Rho-kinase pathway plays an important pathogenetic role in the DES-induced coronary hyperconstricting responses in pigs in vivo.