CHEMICALLY-MODIFIED CARDIAC NA- IS THERE A HIDDEN DRUG RECEPTOR( CHANNELS AND THEIR SENSITIVITY TO ANTIARRHYTHMICS )

Elementary Na+ currents were recorded at 19 degrees C in inside-out pa tches from cultured neonatal rat cardiocytes. In analyzing the sensiti vity of chemically modified Na+ channels to several class 1 antiarrhyt hmic drugs, the hypothesis was tested that removal of Na+ inactivation may be accompanied by a distinct responsiveness to these drugs, open channel blockade. Iodate-modified and trypsin-modified cardiac Na+ cha nnels are noninactivating but strikingly differ from each other by the ir open state kinetics, a O-1-O-2 reaction (tau(open(1)) 1.4 +/- 0.3 m sec; tau(open(2)) 5.4 +/- 1.1 msec; at -40 mv) in the former and a sin gle open state (tau(open) 3.0 +/- 0.5 msec; at -40 mV) in the latter. Lidocaine (150 mu mol/liter) like propafenone (10 mu mol/liter), dipra fenone (10 mu mol/liter) and quinidine (20 mu mol/liter) in cytoplasmi c concentrations effective to depress NPo significantly can interact w ith both types of noninactivating Na+ channels to reduce the dwell tim e in the conducting configuration. Iodate-modified Na+ channels became drug sensitive during the O-2 state. At -40 mV, for example, lidocain e reduced tau(open(2)) to 62 +/- 5% of the control without detectable changes In tau(open(1)). No evidence could be obtained that these inhi bitory molecules would flicker-block the open Na+ pore. Drug-induced s hortening of the open state, thus, is indicative for a distinct mode o f drug action, namely interference with the gating process. Lidocaine proved less effective to reduce tau(open(2)) when compared with the ac tion of diprafenone. Both drugs apparently interacted with individual association rate constants, a(lidocaine) was 0.64 X 10(6) mol(-1) sec( -1) and a(diprafenone) 13.6 X 10(6) mol(-1) sec(-1). Trypsin-modified Na+ channels also appear capable of discriminating among these antiarr hythmics, the ratio a(diprafenone)/a(lidocaine) even exceeded the valu e in iodate-modified Na+ channels. Obviously, this antiarrhythmic drug interaction with chemically modified Na+ channels is receptor mediate d: drug occupation of such a hypothetical hidden receptor that is not available in normal Na+ channels may facilitate the exit from the open state.