Tyrosine kinase inhibitor suppresses the (re)stenotic changes of the coronary artery after balloon injury in pigs

Objective: Restenosis after percutaneous transluminal coronary angioplasty (PTCA) still remains a serious late complication. Many growth factors induced in restenotic lesions may be responsible for restenosis after PTCA. Most of the receptors for such growth factors possess tyrosine kinase activity. This study was designed to determine whether or not a specific tyrosine kinase inhibitor, ST 638, can prevent (re)stenotic changes of the coronary artery after balloon injury. Methods: A segment of the porcine coronary artery was aseptically wrapped with cotton mesh absorbing either ST 638 or vehicle, followed by balloon injury. Two weeks after the procedure, coronary stenosis and vasoconstricting responses were examined by coronary arteriography and (re)stenotic changes of the coronary artery were histologically examined. Antiphosphotyrosine immunoblotting was also performed to examine the inhibitory effects of ST 638. Results: Coronary arteriography showed the development of mild stenotic lesions at the balloon-injured sites, where hyperconstrictive responses were repeatedly induced by intracoronary serotonin and histamine. Histologically, neointimal formation was noted at the balloon-injured site, where the total vessel area also tended to decrease (geometric remodeling). The treatment with ST 638 suppressed all the hyperconstrictive responses, the neointimal formation, and the geometric remodeling induced by balloon injury. Immunoblotting for phosphotyrosine proteins demonstrated the elevation of proteins at the balloon-injured site, which was suppressed by ST 638. Conclusions: These results indicate that tyrosine kinases are activated at the balloon-injured site and the inhibition of such kinase activities is effective in reducing both the (re)stenotic changes (neointimal formation and geometric remodeling) and the hyperconstrictive responses of the coronary artery after balloon injury.