title: In vivo cardiac electrophysiologic and antiarrhythmic effects of an isoquinoline IKur blocker, ISQ-1, in rat, dog, and nonhuman primate.
abstract: 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.
authors: Department of Stroke and Neurodegeneration, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors: Christopher P
authors: CP
authors: Regan
authors: Gary L
authors: GL
authors: Stump
authors: Audrey A
authors: AA
authors: Wallace
authors: Kenneth D
authors: KD
authors: Anderson
authors: Charles J
authors: CJ
authors: McIntyre
authors: Nigel J
authors: NJ
authors: Liverton
authors: Joseph J
authors: JJ
authors: Lynch
mesh_terms: 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
chemical_list: 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