Effects of ambasilide, quinidine, flecainide and verapamil on ultra-rapid delayed rectifier potassium currents in canine atrial myocytes.
OBJECTIVE
A dog atrial ultra-rapid delayed rectifier current (I(Kur. d)) is involved in canine atrial repolarization and shares similarities with the human atrial ultra-rapid delayed rectifier (I(Kur)). Almost no information is available about the actions of antiarrhythmic drugs on I(Kur.d). This study evaluated effects of ambasilide, quinidine, flecainide and verapamil on I(Kur.d) in isolated canine atrial myocytes.


METHODS
Standard whole-cell patch clamp techniques were used to study the effects of multiple concentrations of each drug.


RESULTS
All drugs produced reversible concentration-, voltage- and time-dependent I(Kur.d) inhibition. Significant effects of quinidine, flecainide and ambasilide were noted at atrial-effective antiarrhythmic concentrations in the dog. Upon the onset of a depolarizing pulse, block developed exponentially in relation to time, with the blocking rate-constant increasing with drug concentration, consistent with open-channel blockade and permitting the calculation of forward and reverse rate-constants. For all drugs, the 50% blocking concentration (EC(50)) showed significant voltage-dependence, decreasing at more positive potentials. The magnitude of voltage-dependent block was directly related to the degree of drug-induced shift in the voltage dependence of activation (r=0.97), pointing to open-channel block as a mechanism for voltage-dependent action. An additional component of voltage-dependence suggested that blocking sites were subjected to 17-21% of the transmembrane voltage field.


CONCLUSIONS
Ambasilide, quinidine, flecainide and verapamil inhibit I(Kur.d), with preferential action on the open state. I(Kur.d) inhibition may play a role in antiarrhythmic effects in canine atrial arrhythmia models. Comparisons between the effects of these drugs on I(Kur.d) and previously studied effects on I(Kur) suggest potential opportunities for investigating the molecular structural determinants of drug-blocking action on atrial-specific ultrarapid delayed rectifiers.
Yue
L
L
Department of Pharmacology and Therapeutics, McGill University, Canada.
Feng
J L
JL
Wang
Z
Z
Nattel
S
S
D062365:Aminobenzoates / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005424:Flecainide / Q000494:pharmacology; D006325:Heart Atria; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D011802:Quinidine / Q000494:pharmacology; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
D062365:Aminobenzoates; D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D020746:Calcium Channels, L-Type; D015221:Potassium Channels; C075113:ambasilide; D014700:Verapamil; D011802:Quinidine; D005424:Flecainide