Chemically modified cardiac Na+ channels and their sensitivity to antiarrhythmics: is there a hidden drug receptor?

Abstract

Elementary Na+ currents were recorded at 19 degrees C in inside-out patches from cultured neonatal rat cardiocytes. In analyzing the sensitivity of chemically modified Na+ channels to several class 1 antiarrhythmic 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+ channels are noninactivating but strikingly differ from each other by their open state kinetics, a O1-O2 reaction (tau open(1) 1.4 +/- 0.3 msec; tau open(2) 5.4 +/- 1.1 msec; at -40 mV) in the former and a single open state (tau open 3.0 +/- 0.5 msec; at -40 mV) in the latter. Lidocaine (150 mumol/liter) like propafenone (10 mumol/liter), diprafenone (10 mumol/liter) and quinidine (20 mumol/liter) in cytoplasmic concentrations effective to depress NPo significantly can interact with both types of noninactivating Na+ channels to reduce the dwell time in the conducting configuration. Iodate-modified Na+ channels became drug sensitive during the O2 state. At -40 mV, for example, lidocaine reduced tau open(2) to 62 +/- 5% of the control without detectable changes in tau open(1). No evidence could be obtained that these inhibitory molecules would flicker-block the open Na+ pore. Drug-induced shortening of the open state, thus, is indicative for a distinct mode of drug action, namely interference with the gating process. Lidocaine proved less effective to reduce tau open(2) when compared with the action 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 antiarrhythmics, the ratio a(diprafenone)/a(lidocaine) even exceeded the value in iodate-modified Na+ channels. Obviously, this antiarrhythmic drug interaction with chemically modified Na+ channels is receptor mediated: drug occupation of such a hypothetical hidden receptor that is not available in normal Na+ channels may facilitate the exit from the open state.