I. Benz et M. Kohlhardt, CHEMICALLY-MODIFIED CARDIAC NA- IS THERE A HIDDEN DRUG RECEPTOR( CHANNELS AND THEIR SENSITIVITY TO ANTIARRHYTHMICS ), The Journal of membrane biology, 139(3), 1994, pp. 191-201
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.