GENISTEIN, A TYROSINE KINASE INHIBITOR, REDUCES CA2+ MOBILIZATION IN SWINE CAROTID MEDIA

Di Salvo and colleagues (Biochem. Biophys. Res. Commun. 190: 968-974, 1993) found that tyrosine kinase inhibitors reduced force at constant Ca2+ concentrations in permeabilized mesenteric arterioles. These data suggest that tyrosine kinase activation could regulate Ca2+ sensitivi ty in intact vascular smooth muscle. We tested this hypothesis by exam ining the effects of the tyrosine kinase inhibitor genistein on intrac ellular Ca2+ concentration ([Ca2+](i)), myosin regulatory light chain (MRLC) phosphorylation, and isometric stress in intact swine carotid m edia tissues. Pretreatment with 30 mu M genistein attenuated histamine -induced increases in [Ca2+](i) (estimated using the photoprotein aequ orin), MRLC phosphorylation, and stress. The genistein-dependent decre ase in [Ca2+](i) quantitatively accounted for the decrease in MRLC pho sphorylation and stress. There was no measurable change in the Ca2+ de pendence of MRLC phosphorylation or the dependence of force on MRLC ph osphorylation. Genistein inhibited contractions independently of the s ource of activator Ca2+. These data suggest that tyrosine kinase(s) ma y influence force development in the intact swine carotid media by alt ering [Ca2+](i) rather than modulating the Ca2+ sensitivity of MRLC ph osphorylation.