BLOCKADE OF LYSOPHOSPHATIDYLCHOLINE-MODIFIED CARDIAC NA CHANNELS BY ALIDOCAINE DERIVATIVE QX-222

Single Na channels from rat and rabbit ventricular cells were studied with use of the excised inside-out patch-clamp technique. To investiga te local anesthetic interactions with Na channels modified by the isch emic metabolite lysophosphatidylcholine (LPC), the quaternary ammonium lidocaine derivative QX-222 ethylamino)-N-(2,6-dimethylphenylphenyl)a cetamide] was applied to the cytoplasmic side of patches from untreate d cells and from those treated with LPC for similar to 1 h. Single-cha nnel amplitudes and kinetics for unmodified channels were similar to t hose reported previously for cardiac cells with a single-component, me an-channel open time. LPC-modified channels showed prolonged open chan nel bursting with a two-component, mean open time, suggesting two open states. Conductance sublevels to the 60-70% level of the main conduct ance were found in both unmodified and LPC-modified channels and also with and without QX-222 present. QX-222 reversibly shortened the open time of the unmodified channel and for both open times of the LPC-modi fied channel without decreasing single-channel amplitude. Calculated a ssociation rates for QX-222 with the channel were found to be greater for the open states of the modified channel than those for the unmodif ied channel. Thus the lidocaine analogue QX-222 interacts with and blo cks the open state of both unmodified and LPC-modified, cardiac Na cha nnels. The blocking effect on LPC-modified channels would be predicted to be greater both because of the longer dwell time in the high-affin ity open states for modified channels and also because of an intrinsic ally greater association rate in the modified channels.