TYROSINE KINASE INHIBITOR SUPPRESSES CORONARY ARTERIOSCLEROTIC CHANGES AND VASOSPASTIC RESPONSES INDUCED BY CHRONIC TREATMENT WITH INTERLEUKIN-1-BETA IN PIGS IN-VIVO

We recently demonstrated that chronic treatment with IL-1 beta induces coronary arteriosclerotic changes and vasospastic responses to antaco ids in pigs in vivo and that those responses are importantly mediated by PDGF, The receptors for PDGF and other major growth factors are kno wn to have tyrosine kinase activity, We therefore investigated the eff ects of a selective tyrosine kinase inhibitor, ST 638, on those respon ses induced by IL-1 beta in our swine model, Intimal thickening and co ronary vasospastic responses to serotonin and histamine were induced a t the site of the coronary artery where IL-1 beta was chronically and locally applied, These responses were significantly suppressed in a do se-dependent manner by cotreatment with ST 638, In addition, ST 494, w hich is an inactive form of ST 638, did not inhibit those responses, T he treatment with ST 638 alone did not affect the coronary vasoconstri cting responses to the autacoids, Immunoblotting using an antibody to phosphotyrosines confirmed the inhibitory effects of ST 638 on the tyr osine phosphorylations induced by IL-1 beta, These results thus sugges t that tyrosine kinase activation may play an important role in mediat ing the effects of IL-1 beta, while also suggesting that ST 638 has an inhibitory effect on the arteriosclerotic changes and vasospastic res ponses to autacoids in our swine model in vivo.