Increase In Atrial Refractoriness Research Articles

Electrophysiological Characterization and Antiarrhythmic Efficacy of the Mixed Potassium Channel-Blocking Antiarrhythmic Agent AZ13395438 In Vitro and In Vivo

To examine the electrophysiological, hemodynamic, and antiarrhythmic effects of the novel antiarrhythmic agent AZ13395438. The ion channel-blocking potency of AZ13395438 was assessed in Chinese hamster ovary cells stably expressing various human cardiac ion channels and in human atrial myocytes. The in vivo electrophysiological, hemodynamic, and antiarrhythmic effects of intravenously administered AZ13395438 were examined in anesthetized rabbits, in anesthetized naive dogs, and in dogs subjected to rapid atrial pacing (RAP) for 8 weeks. Pharmacokinetic/pharmacodynamic (PKPD) modeling was applied to predict the potency of AZ13395438 in increasing atrial and ventricular refractoriness. AZ13395438 potently and predominantly blocked the atrial repolarizing potassium currents I(Kur), I(Ach), and I(to) in vitro. In vivo, AZ13395438 caused a concentration-dependent and selective increase in atrial refractoriness with no or small effects on ventricular refractoriness and repolarization and on hemodynamics in both rabbits and dogs. The PKPD modeling predicted unbound plasma concentrations of AZ13395438 of 0.20 ± 0.039, 0.38 ± 0.084, and 0.34 ± 0.057 µmol/L to increase the right atrial effective refractory period by 20 milliseconds in the rabbit and in the naive and the RAP dogs, respectively. In the RAP dog with atrial fibrillation (AF), AZ13395438 significantly increased AF cycle length and successfully converted AF to sinus rhythm in 12 of the 12 occasions at an unbound plasma concentration of 0.48 ± 0.076 µmol/L. During saline infusion, conversion was seen only in 4 of the 10 occasions (P = .003 vs AZ13395438). Furthermore, AZ13395438 reduced AF inducibility by burst pacing from 100% to 25% (P < .001). AZ13395438 can be characterized as a mixed potassium ion channel-blocking agent that selectively prolongs atrial versus ventricular refractoriness and shows promising antiarrhythmic efficacy in a clinically relevant animal model of AF.

In Vivo Cardiac Electrophysiologic Effects of a Novel Diphenylphosphine Oxide IKur Blocker, (2-Isopropyl-5-methylcyclohexyl) Diphenylphosphine Oxide, in Rat and Nonhuman Primate

The voltage-gated potassium channel, Kv1.5, which underlies the ultrarapid delayed rectifier current, I(Kur), is reported to be enriched in human atrium versus ventricle, and has been proposed as a target for novel atrial antiarrhythmic therapy. The administration of the novel I(Kur) blocker (2-isopropyl-5-methyl-cyclohexyl) diphenylphosphine oxide (DPO-1) (0.06, 0.2, and 0.6 mg/kg/min i.v. x 20 min; total doses 1.2, 4.0, and 12.0 mg/kg, respectively) to rat, which exhibits I(Kur) in both atria and ventricle, elicited significant, dose-dependent increases in atrial and ventricular refractory period (9-42%) at all doses tested, with no changes in cardiac rate or indices of cardiac conduction. Plasma levels achieved in rat at the end of the three infusions were 1.1, 4.1, and 7.7 microM. Reverse transcription-polymerase chain reaction analysis of African green monkey atria and ventricle demonstrated an atrial preferential distribution of Kv1.5 transcript. The administration of DPO-1 (1.0, 3.0, and 10.0 mg/kg i.v.; 5-min infusions) to African green monkey elicited significant increases in atrial refractoriness (approximately 15% increase at the 10.0 mg/kg dose), with no change in ventricular refractory period, ECG intervals, heart rate, or blood pressure. Plasma levels of DPO-1 achieved in African green monkey were 0.58, 1.12, and 5.43 microM. The concordance of effect of DPO-1 on myocardial refractoriness with distribution of Kv1.5 in these two species is consistent with the I(Kur) selectivity of DPO-1 in vivo. Moreover, the selective increase in atrial refractoriness in primate supports the concept of I(Kur) blockade as an approach for the development of atrial-specific antiarrhythmic agents.

Electrophysiologic effects of procainamide in subtherapeutic to therapeutic doses on human atrioventricular conduction system

The effects of single intravenous infusions of 50 to 400 mg of procainamide on the functional properties of the atrioventricular (A-V) conduction system were studied in 36 patients and correlated with plasma concentrations. A 50 mg dose of procainamide resulted in a plasma concentration of less than 1.0 μg/ml and produced no electrophysiologic changes. Doses of 100, 200, 300 and 400 mg resulted in progressively increasing plasma concentrations (1.2, 1.8, 3.5 and 4.2 μg/ml, respectively). The effects of procainamide on the sinus rate were variable and not dose-related. The effects of doses of up to 300 mg on A-V nodal conduction were variable and not dose-related. Only in a dose of 400 mg did procainamide prolong A-V nodal conduction in six of seven patients. Whereas 100 mg had no effect on His-Purkinje system conduction, doses of 200, 300 and 400 mg prolonged His-Purkinje system conduction time by 6, 8 and 9 msec, respectively. Dose-related increases in atrial refractoriness started with a dose of 200 mg and became statistically significant with doses of 300 and 400 mg. The effects of procainamide on A-V nodal functional refractoriness were variable and not dose-related, but in doses of 100 to 400 mg, procainamide produced significant and progressively dose-related increases in His-Purkinje system refractoriness. Suppression of some types of ventricular arrhythmia by small doses of this drug may be explained by changes in refractoriness of the His-Purkinje system produced by doses of procainamide as small as 100 mg.