Differential effects of the new class III antiarrhythmic agents almokalant, E-4031 and D-sotalol, and of quinidine, on delayed rectifier currents in guinea pig ventricular myocytes.
OBJECTIVE
The effects of almokalant (4-[3-ethyl[3-(propylsulphinyl)propyl]-amino]-2-hydroxy-propoxy]- benzonitrile), E-4031 (1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4-methylsulphonyl-amino- benzoyl)piperidine), d-sotalol, and quinidine were investigated on the delayed K+ rectifier current IK. The aim of the study was to compare the drug action on the two components of this current.


METHODS
Membrane currents were measured in ventricular myocytes from guinea pig hearts with the whole cell voltage clamp technique. IK was activated during clamp steps from a holding potential of -40 mV to test potentials -30 and +50 mV. The tail current Itail was measured upon stepping back to holding potential.


RESULTS
In control experiments. IK and Itail declined spontaneously ("run down"). With 300 ms long test pulses to +50 mV, only d-sotalol (10(-4) M) caused a significant further decrease in IK, whereas all four agents significantly reduced Itail (almokalant 10(-6) M, E-4031 10(-7) M, quinidine 10(-5) M). When tested with 1 s long clamp steps at various potentials almokalant (3 x 10(-6) M), E-4031 (10(-6) M), quinidine (10(-5) M), and d-sotalol (10(-4) M) reduced IK in the potential range between -20 and +40 mV, yielding a bell shaped inward rectifying drug sensitive current. Itail was reduced by almokalant and E-4031 over the whole voltage range with saturation of block positive to +20 mV. Similar reductions with quinidine but not with d-sotalol were also significant. With rest pulses to +50 mV of increasing duration (25 ms-4000 ms), Itail developed with a faster time course than IK and therefore the ratio of Itail/IK declined with pulse duration. With almokalant and E-4031, this ratio became independent of test pulse duration. For 250 ms pulses, Itail/IK was also significantly reduced by d-sotalol and quinidine.


CONCLUSIONS
Inhibition of the rapidly activating inwardly rectifying component of IK is prominent with almokalant and E-4031 and less pronounced with d-sotalol and quinidine. Since inhibition of this component prolongs the cardiac action potential, it should contribute to the antiarrhythmic properties of the agents.
Wettwer
E
E
Pharmakologisches Institut, Universität-Gesamthochschule-Essen, Germany.
Grundke
M
M
Ravens
U
U
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009132:Muscles / Q000166:cytology; D010880:Piperidines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011802:Quinidine / Q000494:pharmacology*; D013015:Sotalol / Q000494:pharmacology*; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D010880:Piperidines; D015221:Potassium Channels; D011412:Propanolamines; D011725:Pyridines; C063968:E 4031; D013015:Sotalol; C074334:almokalant; D011802:Quinidine; D011188:Potassium