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CARDIOVASCULAR

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

Departments of Stroke (C.P.R., H.K.C., J.J.L.), Medicinal Chemistry (A.A.W.), and Molecular Endocrinology (C.L.A.), Merck Research Laboratories, West Point, Pennsylvania

Received August 29, 2005; accepted October 20, 2005.

	Abstract

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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 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.

By Northern analysis, transcript for the voltage-gated Kv1.5 channel, which underlies the ultrarapid delayed rectifier potassium current, I_Kur, is distributed preferentially in human atrium versus ventricle (Tamkun et al., 1991), and I_Kur current has been recorded in human atrium but not ventricle (Wang et al., 1993; Amos et al., 1996). As a result, block of I_Kur has been suggested as a potential target for atrial selective modulation of refractoriness and prevention/termination of reentrant arrhythmia (Brendel and Peukert, 2003; Hesketh et al., 2005; Pecini et al., 2005). Recently, a series of structurally novel diphenylphosphine oxides (DPOs), represented by the prototype DPO-1, have been reported to block potently human Kv1.5 expressed in Chinese hamster ovary cells as well as native I_Kur in human atrial myocytes (Lagrutta et al., 2004). In the present study, the in vivo cardiac electrophysiologic effects of DPO-1 are characterized in rat, a species in which the Kv1.5 transcript is distributed equally in atrium and ventricle (Roberds and Tamkun, 1991; Dixon and McKinnon, 1994), as well as in the primate Cercopithecus aethiops (African green monkey), which is shown in the present report to display an atrial selective distribution of Kv1.5 transcript similar to that in human. Concordant with the cardiac distribution of Kv1.5 in the test species, DPO-1 increased myocardial refractoriness in both atrium and ventricle of rat but produced an atrial-selective increase in refractoriness in primate.

	Materials and Methods

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All procedures related to the use of animals in these studies were reviewed and approved by the Institutional Animal Care and Use Committee at Merck Research Laboratories (West Point, PA) and conform with the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council, 1996).

In Vivo Studies in Rats. Cardiac electrophysiology (EP) studies were performed in male Sprague-Dawley rats (240-300 g) as described recently (Regan et al., 2005). In brief, rats were anesthetized (ketamine/xylazine 80:5 mg/kg i.p.) and instrumented with catheters in the left femoral vein and artery for infusion of test agent and measurement of mean arterial pressure (MAP), respectively. Octapolar electrode catheters (2F) were advanced near the right atrium via the right jugular vein and into the left ventricle via the right carotid artery to determine cardiac EP parameters. The right atrial electrode catheter was used to pace the heart from the atrium and to determine atrial refractory period (ARP) and atrioventricular (AV) nodal refractory periods. The left ventricular electrode catheter was used to pace the left ventricle directly for the determination of the ventricular refractory period (VRP) and to record His bundle electrograms for the measurement of AH and HV intervals, indices of AV nodal and ventricular conduction, respectively. Refractory periods were determined by extrastimulus technique following a basic train at a rate of 400 beats/min (150-ms cycle length) at 2x excitation threshold. Pin electrodes were attached for the recording of lead II ECG. R-R interval was measured as an index of cardiac rate, and PR interval was measured as an index of AV nodal conduction.

Rat cardiac EP studies with DPO-1 (Aguiar et al., 1976)] used continuous i.v. infusion regimens in separate dosing groups. Following equilibration and baseline readings, DPO-1 was infused continuously at 0.06, 0.2, or 0.6 mg/kg/min i.v. (n = 5, 5, and 4 per group, respectively), with cardiac EP parameters redetermined 20 min after the start of infusion (total doses of 1.2, 4.0, and 12.0 mg/kg, respectively). Blood samples were obtained at baseline and at 20 min after the start of infusion for determination of plasma concentration of DPO-1. Single-dose bolus i.v. pharmacokinetic assessments in rats preceded the design and conduct of the present continuous i.v. infusion studies. Dimethylformamide (DMF; 0.04 µl/g body weight/min) served as the vehicle in rat cardiac EP studies. DMF has been shown previously to have no effect on cardiac EP parameters in this rat preparation (Regan et al., 2005).

RT-PCR Analysis of African Green Monkey Cardiac Tissue. RNA was isolated from atrial and ventricle tissues from two monkeys using the RNeasy kit (QIAGEN, Valencia, CA) after phenol-chloroform extraction to remove the bulk of the protein and genomic DNA. Any additional genomic DNA contamination was removed by digestion with RNase-free DNase (Promega, Madison, WI). Quantification of total RNA was performed by absorption spectrometry. The following polymerase chain reaction primers were designed using Beacon Designer 4 software (PREMIER Biosoft International, Palo Alto, CA): hKCNA5871F, 5'-CGAGGATGAGGGCTTCATTA-3'; hKCNA51056R, 5'-CTGAACTCAGGCAGGGTCTC-3'; actin F, 5'-CCAGCTATGTGTGAAGAGGAAGACAGC-3'; and actin R, 5'-GCT-CAGTCAGGATCTTCATGAGGTAGT-3'. RT-PCR was performed using the OneStep RT-PCR kit (QIAGEN) following manufacturer's guidelines. The following thermocycling parameters were also followed: 50°C for 30 min, 95°C for 15 min (94°C for 1 min and 60°C for 30 s, and 72°C for 30 s for 15 cycles), and 72°C for 10 min. Products were separated on a 2% agarose gel and visualized with ethidium bromide.

In Vivo Studies in African Green Monkeys. African green monkeys (male or female; 3.6-6.7 kg) were anesthetized with 10.0 mg/kg i.m. ketamine hydrochloride followed by 12.5 mg/kg i.v. sodium pentobarbital. The animals were intubated and ventilated with room air. The right femoral vein was cannulated for administration of test agent and supplemental anesthesia, and the right femoral artery was cannulated for measurement of MAP. The right jugular vein was cannulated for blood sampling. A left thoracotomy was performed, and the pericardium incised to expose the heart. A stain-less steel epicardial bipolar electrode was sutured to the right atrium for pacing, and a stainless steel epicardial quadripolar electrode was sutured to the left atrium for recording of atrial electrograms and for determination of atrial excitation threshold (AET) and ARP. A stain-less steel bipolar plunge electrode was sutured to the posterolateral wall of the left ventricle for determination of ventricular excitation threshold (VET) and VRP. Refractory periods were determined by extrastimulus technique at a rate of 180 beats/min (333-ms cycle length) at 2x excitation threshold. Pin electrodes were attached for the recording of lead II ECG. Heart rate and ECG PR, QRS, and QTc (QT in milliseconds/R-R in seconds) were determined during sinus rhythm.

Primate cardiac EP studies with DPO-1 used within-group sequential increasing i.v. dose administration of test agent or vehicle. Following equilibration and baseline readings, DPO-1 was administered as sequential i.v. doses of 1.0, 3.0, and 10.0 mg/kg at 20-min intervals, with each dose administered over a period of 5 min in 5 ml of vehicle (n = 7). ECG intervals and cardiac EP parameters were redetermined both immediately and at 15 min after each test dose. Blood samples were obtained at baseline and both immediately and at 15 min after each test dose for determination of plasma concentration of DPO-1. PEG-200 served as the vehicle in primate cardiac EP studies. In a separate vehicle control group (n = 5), PEG-200 was administered in matching volume and timing to assess vehicle effects on cardiac EP parameters.

Statistics. All data are expressed as mean ± S.E.M. For plasma concentration data, S.D. also was indicated. For the rat studies, which used continuous i.v. infusion regimens of DPO-1 in separate dosing groups, baseline versus post-treatment differences were analyzed using a paired Student's t test. For the primate studies, which used within-group sequential increasing i.v. DPO-1 dose or vehicle administration, test agent effects were analyzed using a two-way analysis of variance (ANOVA), including a within-group repeated measures and a between-group (test agent versus matched vehicle) comparison to detect test agent-specific changes differing significantly from the vehicle profile. If a significant test agent-specific change was indicated, a within-test agent treatment group repeated measures ANOVA followed by a post hoc Fisher's protected least significant difference test was used to identify statistically significant changes from baseline values. For all analyses, p < 0.05 was the criterion for statistical significance.

	Results

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In Vivo Studies in Rats. Table 1 summarizes the cardiac EP effects of 20-min continuous i.v. infusions of 0.06, 0.20, or 0.60 mg/kg/min DPO-1 (1.2, 4, and 12 mg/kg total dose, respectively) in anesthetized rats. Infusion of DMF vehicle did not cause significant changes in cardiac conduction or refractoriness (data not shown). DPO-1 caused significant, dose-dependent increases in atrial (12-42%) and ventricular (9-34%) refractory periods in rat with threshold effects on both parameters occurring with the low 0.06 mg/kg/min in-fusion dose. There were no significant changes in cardiac rate, AV nodal, or ventricular conduction parameters at any doses tested. However, there was a slight (5%) but statistically significant increase in AV nodal refractory period at the highest dose tested. Of note, there was no significant increase in MAP until the highest dose tested. Interestingly, the increase in MAP at this dose was driven by a selective increase in systolic pressure in the rat. Plasma levels of DPO-1 determined at the end of the 20-min continuous 0.06, 0.20, or 0.60 mg/kg/min i.v. infusions in the anesthetized rats were 1.1 ± 0.3 (S.D. 0.7) µM, 4.1 ± 0.5 (S.D. 1.2) µM, and 7.7 ± 1.5 (S.D. 3.0) µM, respectively.

RT-PCR Analysis of African Green Monkey Cardiac Tissue. RT-PCR analysis of African green monkey atria and ventricle was performed to determine the relative expression level of Kv1.5 in atria versus ventricle in this species. RT-PCR was performed multiple times on atrial and ventricular RNA isolated from two African green monkeys. Figure 1 is a representative gel from one of those studies. As seen in Fig. 1, RT-PCR analysis revealed a significant expression of Kv1.5 in African green monkey atria with limited expression detected in the ventricle.

View larger version (56K): [in this window] [in a new window]   Fig. 1. RT-PCR analysis of Kv1.5 transcript in African green monkey atria and ventricle showing enhanced expression of Kv1.5 transcript in atria versus ventricle. Amplification of actin (top band) served as internal control.

View larger version (22K): [in this window] [in a new window]   Fig. 2. Effects of sequential i.v. dose administration of DPO-1 or vehicle (PEG-200) on ARP and VRP, expressed as percentage of change from baseline, in anesthetized African green monkeys. Absolute values for these parameters are in Tables 2 and 3.

	Discussion

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AF is the most common chronic cardiac arrhythmia, with a prevalence in the United States estimated at 2.2 million (American Heart Association, 2005). AF is associated with increased risk of stroke, including stroke recurrence and severity, heart failure, and increased mortality (Benjamin et al., 1998; Stewart et al., 2002; Penado et al., 2003). In the Framingham Heart Study, the lifetime risk for development of AF has been estimated to be one in four for both men and women 40 years of age and older, with lifetime risks for AF of one in six even in the absence of antecedent congestive heart failure or myocardial infarction (Lloyd-Jones et al., 2004). The prevalence, rate of hospitalization, and economic burden of AF are increasing, driven by an aging population as well as improved survival from underlying conditions predisposing to AF (Greenlee and Vidaillet, 2004; Stewart et al., 2004).

Underscoring the inadequacy of currently available anti-arrhythmic agents for the treatment of AF, clinical trials comparing atrial rhythm control with presently available antiarrhythmic agents versus ventricular rate control have reported no benefit in mortality, morbidity, or quality of life benefit with current rhythm control therapy, with a higher incidence for adverse drug effects with rhythm control anti-arrhythmic drugs (The AFFIRM Investigators, 2002; Van Gelder et al., 2002). Modest efficacy and the potential for significant adverse effects, including ventricular proarrhythmia, have been cited repeatedly as contributing factors for the lack of benefit of rhythm control with currently available antiarrhythmic drugs.

Blockade of the atrial-selective ultrarapid delayed rectifier current, I_Kur, encoded by the Kv1.5 channel, has been proposed as a novel target for the development of safer and potentially more effective atrial antiarrhythmic agents (Brendel and Peukert, 2003; Hesketh et al., 2005; Pecini et al., 2005). Three structurally distinct antiarrhythmic agents have been described as possessing I_Kur block as part of their spectra of actions: NIP-141/142 (Matsuda et al., 2001), AVE0118 (Gogelein et al., 2004), and RSD1235 (Beatch et al., 2003; Beatch and Ezrin, 2004). However, the aforementioned compounds display 3-fold or less selectivity for Kv1.5 and I_Kur over other cardiac K⁺ channels, including rapidly activating component of delayed rectifier potassium current, transient outward potassium current, and G-protein regulated, muscarinic-activated potassium current (Matsuda et al., 2001; Seki et al., 2002; Beatch et al., 2003; Brendel and Peukert, 2003; Gogelein et al., 2004; Fedida et al., 2005).

DPO-1 is representative of a novel DPO I_Kur blocker pharmacophore. In Chinese hamster ovary cells transfected with human Kv1.5, DPO-1 inhibited human Kv1.5 current in a forward frequency-dependent manner, with IC₅₀ values of 0.16, 0.05, and 0.03 µM at pacing frequencies of 0.1, 1.0, and 3.0 Hz, respectively (Lagrutta et al., 2004). In isolated human atrial myocytes, DPO-1 inhibited I_Kur with IC₅₀ values of 0.08, 0.04, and 0.03 µM at pacing frequencies of 0.1, 1.0, and 3.0 Hz, respectively. At a test concentration of 1.0 µM, DPO-1 failed to inhibit transient outward potassium current in isolated human atrial myocytes. In isolated guinea pig ventricular myocytes, DPO-1 at a test concentration of 3.0 µM elicited minimal-to-no block of other cardiac K⁺ currents: 15% block of inward rectifier potassium current, 3% block of rapidly activating component of delayed rectifier potassium current, and 25% block of slowly activating component of delayed rectifier potassium current (Lagrutta et al., 2004).

In the present study, the in vivo cardiac electrophysiologic effects of DPO-1 were assessed in two species with varying distribution of Kv1.5. In vivo in rat, a species in which Kv1.5 mRNA and I_Kur current are found in both atrium and ventricle (Apkon and Nerbonne, 1991; Boyle and Nerbonne, 1991; Roberds and Tamkun, 1991; Dixon and McKinnon, 1994), DPO-1 produced dose-dependent and concomitant increases in atrial and ventricular refractory periods. In the dosage range tested, there were no significant effects on cardiac rate, or ECG and cardiac EP indices of cardiac conduction. A slight increase in AV nodal refractoriness was detected in rat with the high dose of DPO-1. However, given that the method used for measurement of AV node refractory period involves measurement of a ventricular response after insertion of a premature atrial extrastimulus, the slight increase in AV refractoriness may have reflected increases in atrial and/or ventricular refractoriness.

Although expression of Kv1.5 and the presence of I_Kur current has been shown to be enriched in the atria of human (Tamkun et al., 1991; Wang et al., 1993; Amos et al., 1996), there are little-to-no data available in nonhuman primate heart. Therefore, we performed an RT-PCR analysis of African green monkey atria and ventricles to determine the relative expression level of Kv1.5. RT-PCR analysis on atrial and ventricular RNA isolated from two African green monkeys indicated an atrial preferential distribution of the transcript for the Kv1.5 channel, similar to that reported in human. In vivo in the African green monkey, DPO-1 produced a dose-dependent increase in atrial refractoriness, with no significant change in ventricular refractoriness or ECG QTc interval. In the dosage range tested, there were no significant effects on heart rate, ECG or cardiac EP indices of atrial and ventricular excitability, AV nodal or ventricular conduction distinct from vehicle effects.

In a separate study, the in vivo cardiac electrophysiologic effects of DPO-1 have been assessed in a canine model of intracaval and right atrial surgical lesions producing the anatomic substrate for reentrant atrial arrhythmia. In this canine arrhythmia model, i.v. doses of DPO-1 that were effective in terminating atrial arrhythmia were associated with significant increases in atrial refractoriness but no changes in ECG PR, QRS, and QTC intervals and no change in ventricular refractoriness (Stump et al., 2005). These findings in the canine further suggest modulation by DPO-1 of an atrial-selective target. Consistent with this finding, recent evidence indicates that dog atrium possesses Kv1.5 protein and functionally important I_Kur (Fedida et al., 2003).

The concordance of chamber selectivity of DPO-1 effect on myocardial refractoriness with Kv1.5 transcript distribution in the two test species used in the present studies, rat and African green monkey, supports the argument that the observed effects on myocardial refractoriness resulted from I_Kur block. The lack of effects of DPO-1 on indices of myocardial excitability and conduction suggest I_Kur plays a relatively selective role in modulating myocardial action potential duration and refractoriness in the species. It is noteworthy that, in African green monkey, DPO-1 elicited significant increases in atrial refractory periods in the absence of effects on mean arterial pressure distinct from vehicle effects. In rat, at lower test doses, DPO-1 produced significant increases in atrial and ventricular refractoriness in the absence of significant effects on mean arterial pressure, whereas increased blood pressure, driven by selective increases in systolic pressure, was observed in rat at higher dose. However, the presence of I_Kur in rat ventricle with the attendant potential for effects on ventricular function through modulation of ventricular repolarization complicates the interpretation of hemodynamic effects in this species. The selective increase in systolic blood pressure with high-dose DPO-1 may reflect an increase in ventricular contractility due to the significant delay in repolarization. Alternately, the selective increase in systolic pressure may reflect a direct vasoconstrictive effect of DPO-1, as there is considerable literature suggesting the presence of and role for Kv channels, including Kv1.5, in the regulation of vascular tone (Smirnov et al., 2003). The ability of DPO-1 to increase atrial refractory period without significant effect on blood pressure in the primate as well as to increase myocardial refractoriness with no significant effect on blood pressure at lower doses in rats suggests the possibility to modulate atrial refractoriness without untoward systemic hemodynamic effects via block of I_Kur. In addition, several marketed compounds in a variety of therapeutic classes block Kv1.5 in clinically relevant concentrations, suggesting no inherent detrimental effect of I_Kur block per se. (Brendel and Peukert, 2003). Ultimately, a definitive assessment of the efficacy of I_Kur blockade in modulating atrial refractoriness vis a vis potential vascular effects requires the clinical assessment of a selective I_Kur blocker.

Two limitations of the present study merit mention. Re-fractory period determinations in the present rat and primate studies were conducted at fixed pacing cycle lengths of 150 and 333 ms, respectively. A more extensive assessment of the frequency dependence of effects of either DPO-1, or a more advanced selective I_Kur blocker, on atrial versus ventricular refractoriness is warranted and required to better characterize the chamber selectivity of these agents. In addition, the present studies in rat and primate assessed the cardiac electrophysiologic effects of DPO-1 at plasma concentrations up to approximately 5 to 7 µM. It cannot be precluded that higher plasma levels of this test agent might reveal a different profile of activity.

In summary, in rat and African green monkey, the I_Kur blocker DPO-1 in the dosage ranges tested produced increases in atrial and ventricular refractoriness concordant with distribution of Kv1.5. Increases in myocardial refractoriness were achieved in the absence of changes in ECG or cardiac EP indices of atrial and ventricular excitability, atrioventricular nodal, or ventricular conduction. In African green monkey, DPO-1 produced increases in atrial refractory period in the absence of significant effects on ventricular refractory period and ECG QTc or mean arterial pressure. These findings further support blockade of the Kv1.5 channel as a potential target for modulation of atrial refractoriness and the treatment of atrial arrhythmia.

	Footnotes

 
doi:10.1124/jpet.105.094839.

ABBREVIATIONS: AF, atrial fibrillation; I_Kur, ultrarapid delayed rectifier potassium current; DPO, diphenylphosphine oxide; DPO-1, (2-isopropyl-5-methylcyclohexyl) diphenylphosphine oxide; EP, electrophysiology; MAP, mean arterial pressure; ARP, atrial refractory period; AV, atrioventricular; VRP, ventricular refractory period; DMF, dimethylformamide; RT-PCR, reverse transcription-polymerase chain reaction; AET, atrial excitation threshold; VET, ventricular excitation threshold; PEG, polyethylene glycol; ANOVA, analysis of variance.

Address correspondence to: Dr. Joseph J. Lynch, WP46-300, Merck Research Laboratories, West Point, PA 19486. E-mail: joseph_lynch{at}merck.com

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