Dilazep inhibits binding of batrachotoxin to sodium channels in canine sarcolemmal vesicles.
We studied the effect of dilazep on the binding of [3H]- batrachotoxinin A 20 alpha-benzoate ([3H]BTXB), which binds to and stabilizes the activated state of the Na+ channel, and compared it with that of lidocaine in canine cardiac sarcolemmal vesicles. Dilazep inhibited the specific [3H]BTXB binding in a dose-dependent manner with an IC50 value of 0.37 microM, while lidocaine inhibited it with an IC50 value of 92 microM. Scatchard analysis of [3H]BTXB binding demonstrated that both dilazep and lidocaine reduced the amax without a marked effect on the K(D). The inhibition of [3H]BTXB induced by dilazep was reversible. Both dilazep (4 microM) and lidocaine (100 microM) increased the dissociation rate constant of [3H]BTXB only in concentrations which are about a 10-fold greater than their IC50, indicating the low affinity of both drugs for the [3H]BTXB-bound Na+ channel. However, dilazep (0.5 microM) and lidocaine (100 microM) decreased significantly the association rate constant of the [3H]BTXB binding at concentrations near their IC50, indicating that the affinity of both drugs for the [3H]BTXB-unbound Na+ channel is relatively high. These results suggest that, in canine cardiac membrane vesicles, the effect of dilazep in inhibiting the binding of [3H]BTXB and stabilizing the Na+ channel is similar to that of lidocaine, but the potency of dilazep is greater than that of lidocaine.
Chiba
K
K
Department of Hospital Pharmacy, Asahikawa Medical College, Asahikawa, Japan.
Hashizume
H
H
Inagaki
S I
SI
Abiko
Y
Y
D000157:Aconitine / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents; D001496:Batrachotoxins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004109:Dilazep / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D008012:Lidocaine; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D012508:Sarcolemma / Q000187:drug effects* / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D001496:Batrachotoxins; D015222:Sodium Channels; D014665:Vasodilator Agents; D008012:Lidocaine; D004109:Dilazep; D000157:Aconitine