Effects of dofetilide and EGIS-7229, an antiarrhythmic agent possessing class III, IV, and IB activities, on myocardial refractoriness in hyperkalemia, hypokalemia, and during beta-adrenergic activation in the rabbit papillary muscle in vitro.
Lengthening of the effective refractory period (ERP) by EGIS-7229, a class III/Ib/IV drug, and by dofetilide, a selective I(Kr) blocker, was compared in normokalemia (NK), hypokalemia (LK), and hyperkalemia (HK) in right ventricular papillary muscles of rabbits paced at 0.5, 1, and 2 Hz, in vitro, and also during beta-adrenergic activation. In NK, EGIS-7229 (3 and 10 microM) and dofetilide (30 and 100 nM) similarly lengthened ERP in a steeply reverse frequency-dependent manner. The two compounds produced smaller ERP prolongations at 0.5 Hz in HK and LK, so rate-dependence of ERP changes decreased. EGIS-7229 lengthened ERP more at 2 Hz than at 0.5 Hz at 10 microM in LK, that is, the effect of EGIS-7229 turned into positive frequency-dependence from 3 to 10 microM. Furthermore, EGIS-7229 lengthened ERP at 10 microM more than dofetilide at 100 nM at 2 Hz stimulation rate (P<0.05). Isoproterenol (30 nM) eliminated the effect of dofetilide on ERP, while EGIS-7229 prolonged ERP during beta-adrenergic activation. In conclusion, efficacy of EGIS-7229 was superior to that of dofetilide in LK and during beta-adrenergic stimulation, suggesting improved antiarrhythmic action for EGIS-7229 under certain conditions in the patient.
Kovács
Anikó
A
Pharmacology Laboratory I, EGIS Pharmaceuticals, Ltd., Hungary.
Szénási
Gábor
G
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004562:Electrocardiography; D006947:Hyperkalemia / Q000378:metabolism; D007008:Hypokalemia / Q000378:metabolism; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction; D010210:Papillary Muscles / Q000187:drug effects* / Q000378:metabolism; D010627:Phenethylamines / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D000889:Anti-Arrhythmia Agents; C106729:EGIS 7229; D010627:Phenethylamines; D011724:Pyridazines; D013449:Sulfonamides; D007545:Isoproterenol; C063533:dofetilide