Effects of the new class III antiarrhythmic drug E-4031 on myocardial contractility and electrophysiological parameters.
The effects of the new class III antiarrhythmic agent E-4031 were investigated in different guinea pig cardiac preparations. In left atria, E-4031 (10(-8)-10(-5) M) prolonged the functional refractory period up to 45% and reduced the frequency of spontaneously beating right atria by 32%. In papillary muscles, E-4031 (3 x 10(-8)-3 x 10(-7) M) reversibly prolonged the action potential duration (APD70) of fast and slow APs by 68 and 51%, respectively. Vmax, resting potential, and AP amplitude (APA) were not altered. In isolated ventricular myocytes, E-4031 reversibly prolonged the APD90 from 275 ms (control) to 1,496 ms (10(-6) M), pD2 value 6.5. The current changes that underlie the AP-prolonging effect were also studied in ventricular myocytes: in concentrations up to 10(-5) M), E-4031 did not affect the Na+ or Ca2+ inward current but reduced the delayed rectifier (IK) tail current by 76% (10(-7) M). Contractility was enhanced by E-4031 in isolated atria by 20% (3 x 10(-7) M) and increased cell shortening in ventricular myocytes. Thus, the class III antiarrhythmic action of E-4031 is due to a selective reduction of outward currents.
Wettwer
E
E
Pharmakologisches Institut, Medizinische Einrichtungen der Universität-Gesamthochschule, Essen, F.R.G.
Scholtysik
G
G
Schaad
A
A
Himmel
H
H
Ravens
U
U
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D007473:Ion Channels; D010880:Piperidines; D011725:Pyridines; C063968:E 4031; D011188:Potassium; D002118:Calcium