[Quantitative studies on dauricine block of cardiac sodium channels].
Quantitative studies on kinetics of dauricine (Dau) blockade of cardiac sodium channels based on the model of gate-related receptor hypothesis were performed by using computer simulation. The time constant of recovery from blocking of Dau at holding potential -80 mV was 9.8 s and increased with membrane potential hyperpolarization, which suggested that Dau might be trapped in channel by activation gate. The apparent rate of onset of blocking of Dau was 0.33/pulse at stimulation frequency of 1.0 Hz. These results showed that Dau blocks sodium channel in a fast-in-slow-out (FISO) fashion. The binding rate of drug-receptor at clamping potential -50 mV was 753 kL.mol-1.s-1, the unbinding rate was 32.86/s, with Kd of 44 mumol.L-1 which coincided reasonably with documented IC50 value of 46 mumol.L-1 for inhibition of sodium current. The studies also showed a shift by -4 mV on the mid-point of h infinity curve. All these studies lead us to suggest that the binding site of Dau in cardiac sodium channel is activation gate-related receptor site.
Wu
Y J
YJ
Department of Pharmacology, Tongji Medical University, Hankou, China.
Fang
D C
DC
D000470:Alkaloids; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D044182:Benzylisoquinolines; D003198:Computer Simulation; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects; D044005:Tetrahydroisoquinolines
D000470:Alkaloids; D000889:Anti-Arrhythmia Agents; D044182:Benzylisoquinolines; D007546:Isoquinolines; D015222:Sodium Channels; D044005:Tetrahydroisoquinolines; C035934:dauricine