title: Sodium channel states control binding and unbinding behaviour of antiarrhythmic drugs in cardiac myocytes from the guinea pig.
abstract: OBJECTIVE
  The aim was to investigate whether cardiac sodium channel states (rested, activated, inactivated) regulate the binding and unbinding behaviour of antiarrhythmic drugs on the receptor sites.
  
  
  METHODS
  Single ventricular myocytes of adult guinea pig heart were obtained by an enzymatic dissociation method in the Langendorff manner. The channel state dependent blocking effects on cardiac sodium current (INa) of quinidine and disopyramide were studied under the whole cell variation of the patch clamp technique.
  
  
  RESULTS
  10 microM quinidine and 20 microM disopyramide produced similar levels of tonic block and use dependent block. The steady state inactivation curve (h infinity curve) was shifted parallel in the negative potential direction by quinidine (10 microM) and disopyramide (20 microM) to the same extent (-10 mV). Removal of the fast inactivation process of INa by chloramine-T did not reduce tonic and use dependent block by these drugs. Onset block study using a double pulse protocol revealed that block developments by both drugs were fitted to the sum of double exponential functions. However, time constant of fast phase of block by disopyramide was faster than that by quinidine, while slow phase was not significantly different. Definition of time courses of unbinding (recovery) at -140 mV indicated that quinidine dissociated relatively slowly as compared to disopyramide.
  
  
  CONCLUSIONS
  Quinidine produces more potent tonic and use dependent block of INa by binding to sodium channels at both rested and inactivated states, while disopyramide has a higher affinity for activated state. Therefore, sodium channel states regulate the binding and unbinding behaviour of antiarrhythmic drugs. Furthermore, the fast inactivation process is not essential in producing tonic and use dependent block by antiarrhythmic drugs.
authors.affiliation: First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Koumi
authors.forename: R
authors.initials: R
authors.lastname: Sato
authors.forename: R
authors.initials: R
authors.lastname: Katori
authors.forename: I
authors.initials: I
authors.lastname: Hisatome
authors.forename: K
authors.initials: K
authors.lastname: Nagasawa
authors.forename: H
authors.initials: H
authors.lastname: Hayakawa
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism*; D002478:Cells, Cultured; D004206:Disopyramide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011802:Quinidine / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000889:Anti-Arrhythmia Agents; D015222:Sodium Channels; D004206:Disopyramide; D011802:Quinidine