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-isopr...

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Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2006-02, Vol.316 (2), p.727-732
Main Authors: Regan, Christopher P, Wallace, Audrey A, Cresswell, Hillary K, Atkins, Charity L, Lynch, Jr, Joseph J
Format: Article
Language:English
Subjects:
Animals
Anti-Arrhythmia Agents - pharmacology
Blood Pressure - drug effects
Cercopithecus aethiops
Dose-Response Relationship, Drug
Electrophysiology
Female
Heart - drug effects
Heart - physiology
Heart Atria - drug effects
Heart Atria - metabolism
Heart Rate - drug effects
Heart Ventricles - drug effects
Heart Ventricles - metabolism
Kv1.5 Potassium Channel - metabolism
Male
Myocardium - metabolism
Phosphines - pharmacology
Potassium Channel Blockers - pharmacology
Rats
Species Specificity
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Summary: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. × 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 μM. 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 μM. 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.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.105.094839