In vivo cardiac electrophysiologic and antiarrhythmic effects of an isoquinoline IKur blocker, ISQ-1, in rat, dog, and nonhuman primate

J Cardiovasc Pharmacol. 2007 Apr;49(4):236-45. doi: 10.1097/FJC.0b013e3180325b2a.

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.

MeSH terms

  • Analysis of Variance
  • Animals
  • Anti-Arrhythmia Agents / blood
  • Anti-Arrhythmia Agents / pharmacology
  • Arrhythmias, Cardiac / drug therapy*
  • Arrhythmias, Cardiac / physiopathology*
  • Atrial Flutter / drug therapy
  • Atrial Flutter / physiopathology
  • Atrial Function / drug effects
  • Blood Pressure / drug effects
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Dogs
  • Dose-Response Relationship, Drug
  • Electrophysiologic Techniques, Cardiac*
  • Female
  • Heart Conduction System / drug effects
  • Heart Conduction System / physiopathology
  • Heart Rate / drug effects
  • Infusions, Intravenous
  • Isoquinolines / blood
  • Isoquinolines / pharmacology*
  • Male
  • Potassium Channel Blockers / blood
  • Potassium Channel Blockers / pharmacology*
  • Primates*
  • Rats
  • Rats, Sprague-Dawley
  • Refractory Period, Electrophysiological / drug effects
  • Time Factors

Substances

  • 3-((dimethylamino)methyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one
  • Anti-Arrhythmia Agents
  • Isoquinolines
  • Potassium Channel Blockers
  • isoquinoline