In vivo cardiac electrophysiologic and antiarrhythmic effects of an isoquinoline IKur blocker, ISQ-1, in rat, dog, and nonhuman primate.
The cardiac electrophysiologic effects of ISQ-1, an isoquinolinone I(Kur) blocker, were characterized in vivo. In rat, ISQ-1 elicited maximal 33% to 36% increases in atrial and ventricular refractoriness at a plasma concentration of 11.5 microM. In African green monkey, ISQ-1 increased atrial refractory period (maximal 17% at plasma concentration up to 20 microM) with no effect on ventricular refractory period or ECG QTc. Likewise in dog, ISQ-1 increased atrial refractory period (maximal 16% at plasma concentration up to 2 microM) with no effect on ventricular refractory period or QTc. In contrast, studies with ibutilide in nonhuman primate and dog demonstrated concomitant increases in atrial and ventricular refractoriness and QTc. Additionally, in a dog model of atrial flutter, ISQ-1 terminated ongoing flutter at doses (2.5 +/- 0.5 mg/kg IV) that selectively prolonged atrial refractoriness (13% increase), whereas flutter termination with ibutilide occurred at doses that increased both atrial and ventricular refractoriness as well as QTc. Of note, the cardiac electrophysiologic profiles displayed by ISQ-1 in these species were similar to those reported previously by our lab with a structurally distinct I(Kur) blocker. Taken together, these results further support the inhibition of I(Kur) as an approach to terminate atrial arrhythmia.
Regan
Christopher P
CP
Department of Stroke and Neurodegeneration, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Stump
Gary L
GL
Wallace
Audrey A
AA
Anderson
Kenneth D
KD
McIntyre
Charles J
CJ
Liverton
Nigel J
NJ
Lynch
Joseph J
JJ
D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000503:physiopathology*; D001282:Atrial Flutter / Q000188:drug therapy / Q000503:physiopathology; D016275:Atrial Function / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D007546:Isoquinolines / Q000097:blood / Q000494:pharmacology*; D008297:Male; D026902:Potassium Channel Blockers / Q000097:blood / Q000494:pharmacology*; D011323:Primates; D051381:Rats; D017207:Rats, Sprague-Dawley; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013997:Time Factors
C522538:3-((dimethylamino)methyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one; D000889:Anti-Arrhythmia Agents; D007546:Isoquinolines; D026902:Potassium Channel Blockers; C039109:isoquinoline