Density and kinetics of I(Kr) and I(Ks) in guinea pig and rabbit ventricular myocytes explain different efficacy of I(Ks) blockade at high heart rate in guinea pig and rabbit: implications for arrhythmogenesis in humans.
BACKGROUND
Class III antiarrhythmic agents commonly exhibit reverse frequency-dependent prolongation of the action potential duration (APD). This is undesirable because of the danger of bradycardia-related arrhythmias and the limited protection against ventricular tachyarrhythmias. The effects of blockade of separate components of delayed rectifier K(+) current (I(K)) may help to develop agents effective at high heart rate.


RESULTS
We assessed the density and kinetics of the 2 components of the delayed rectifier K(+) current, I(Kr) and I(Ks), in rabbit and guinea pig ventricular myocytes. The effects of their specific blockers (chromanol 293B for I(Ks) and E-4031 for I(Kr)) on the action potential was studied at different heart rates by use of whole-cell patch-clamp techniques. In guinea pig ventricular myocytes only, blockade of I(Ks) causes APD prolongation in a frequency-independent manner, whereas blockade of I(Ks) in rabbit ventricular myocytes shows reverse frequency dependence, as does blockade of I(Kr) in both species. This result can be explained primarily by the higher density of I(Ks) in guinea pig ventricle and by its slow deactivation kinetics, which allows I(Ks) to accumulate at high heart rate because little time is available for complete deactivation of it during diastole.


CONCLUSIONS
Density and kinetics of components of I(K) explain why blockade of I(Ks) is more effective at high heart rate in the guinea pig ventricle than in the rabbit ventricle, without adverse effects at low heart rate.
Lu
Z
Z
Department of Circulation, Division of Regulation of Organ Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
Kamiya
K
K
Opthof
T
T
Yasui
K
K
Kodama
I
I
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D013449:Sulfonamides; C063968:E 4031; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane