Rate-dependent class III antiarrhythmic action, negative chronotropy, and positive inotropy of a novel Ik blocking drug, UK-68,798: potent in guinea pig but no effect in rat myocardium.
The electromechanical effects of UK-68,798 (UK), a novel class III antiarrhythmic drug, were studied in guinea pig and rat papillary muscles (PMs) and atria in vitro using conventional microelectrode technique. UK (10(-8)-10(-6) M) prolonged the action potential duration (APD) by 21-58% and effective refractory period in parallel, without affecting the resting potential or maximum rate of depolarization in guinea pig PM stimulated at 1 Hz. UK increased the contractile force without prolonging the time to peak force or relaxation. In comparison, 5 x 10(-5) M d-sotalol was needed to induce the same electrophysiological effects as 10(-8) M UK. UK prolonged the APD significantly less at 2 Hz than at 1 and 0.5 Hz. Early afterdepolarizations (EADs) developed in 2 of 11 preparations after 10(-6) M at 0.5 Hz. No reversal of drug effect was seen after up to 2 h washout. UK (10(-9)-10(-5) M) reduced the spontaneous heart rate and prolonged the sinus node recovery time of guinea pig right atria. No effects on rat PM or atria, even after 10(-5) M, indicate a selective action of UK on the delayed rectifying outward potassium current, Ik. These results indicate a potent and selective, rate-dependent class III antiarrhythmic action of UK-68,798 linked with positive inotropy. Increased APD, bradycardia, and induction of EADs, however, represent a potential arrhythmogenic combination.
Tande
P M
PM
Department of Medical Physiology, Institute of Medical Biology, University of Tromsø, Norway.
Bjørnstad
H
H
Yang
T
T
Refsum
H
H
D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects; D010627:Phenethylamines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D015222:Sodium Channels / Q000187:drug effects; D013015:Sotalol / Q000494:pharmacology; D013045:Species Specificity; D013268:Stimulation, Chemical; D013449:Sulfonamides / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D015222:Sodium Channels; D013449:Sulfonamides; D013015:Sotalol; C063533:dofetilide