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

摘要

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 mu M.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 mu M.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.