ELECTROPHYSIOLOGICAL AND INOTROPIC CHARACTERIZATION OF A NOVEL CLASS-III ANTIARRHYTHMIC AGENT, GLG-V-13, IN THE MAMMALIAN HEART

GLG-V-13, a novel 3,7-diheterabicyclo(3.3.1)nonane, was examined both in vivo and in vitro to characterize its electrophysiological, hemodyn amic, and inotropic properties. In anesthetized guinea pigs, GLG-V-13 [0.5-500 mu g/kg intravenously (i.v.), n = 6] lengthened the epicardia l monophasic action potential (MAP) duration, the atrioventricular (AV ) conduction rime and the RR interval in a dose-dependent manner. At t he highest dose, these variables were increased by 30, 13, and 23%, re spectively. No significant effects were noted on QRS duration or blood pressure (BP). III rabbit atrial and papillary muscle preparations, G LG-V-13 (0.32-3.2 mg/L) did not exert a negative inotropic action and in isolated rabbit cardiomyocytes the agent blocked the rapidly activa ting delayed rectifier K+ current (I-Kr, EC(50) = 48 mu g/L) In 10 int act anesthetized mongrel dogs, the left ventricular (LV) endocardial M AP was measured during atrial pacing before and after administration o f GLG-V-13 (3 and 6 mg/kg i.v.). As compared with the drug-free state, the agent induced a significant prolongation of the MAP at all pacing frequencies (2.0-4.5 Hz), In 15 anesthetized dogs studied 1-4 days af ter two-stage ligation of the left anterior descending coronary artery (LAD), the antiarrhythmic/proarrhythmic potential of GLG-V-13 was com pared with that of lidocaine. EGG, His bundle, LV (IZ(epi)), and compo site and normal zone composite electrograms were recorded. Programmed electrical stimulation (PES) and burst pacing (4.0-7.0 Hz) were delive red to the right ventricular outflow tract. In the drug-free state, su stained monomorphic ventricular tachycardia (SMVT) was inducible in 6 dogs (6 of 15). After lidocaine. SMVT was induced in 7 other dogs (13 of 15). GLG-V-13 prevented induction of SMVT in 5 of 6 dogs; a proarrh ythmic action was noted in 1 dog only. GLG-V-13 slowed the heart rate (HR), increased the AH and the HV intervals. prolonged the paced (2.5 Hz) QT interval, and increased the ventricular effective refractory pe riod (VERP). These effects were associated with 2:1 block of late pote ntials in the IZ(epi) electrograms, a phenomenon also observed during rapid atrial pacing (2.5-3.5 Hz), suggestive of a marked prolongation of refractoriness in the ischemically damaged myocardium. In light of the recent Cardiac Arrhythmia Suppression Trial (CAST) study, the anti arrhythmic efficacy. together with the low proarrhythmic potential and lack of cardiodepressant proper-ties of GLG-V-13, may merit further i nvestigation of this novel class III antiarrhythmic agent.