TYROSINE KINASE INHIBITION REDUCES I(F) IN RABBIT SINOATRIAL NODE MYOCYTES

We studied pacemaker current (i(f)), the inward current activated by h yperpolarization in rabbit sinoatrial (SA) node myocytes, with the per meabilized-patch-clamp technique. The tyrosine kinase inhibitors genis tein (50 mu M) or herbimycin A (35 mu M) reduced the amplitude of i(f) in response to step hyperpolarizations in the diastolic range of pote ntials. A two-step voltage-clamp protocol revealed that the reduction in i(f) is due to a decrease in maximal i(f) conductance. The observed effects are due to tyrosine kinase inhibition since an inactive analo g of genistein did not reduce i(f). To further examine the mechanism o f action, we added 2 mM chlorophenylthio cAMP (CPTcAMP, a membrane-per meant cAMP analog) to the bathing Tyrode, which increased i(f). Genist ein still reduced i(f) in the presence of CPTcAMP. This suggests that the pathway mediating the actions of tyrosine kinase inhibition on i(f ) is independent of cAMP- or protein-kinase-A-mediated phosphorylation .