(Circulation. 1999;100:2437.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Systemic Administration of Calmodulin Antagonist W-7 or Protein Kinase A Inhibitor H-8 Prevents Torsade de Pointes in Rabbits
From the Departments of Medicine (A.M., D.M.R., M.E.A.) and Pharmacology (D.M.R., M.E.A.), Vanderbilt University Medical Center, Nashville, Tenn. This work was performed to fulfill requirements for cardiology certification in Israel for Dr Mazur.
Correspondence to Mark Anderson, MD, PhD, Vanderbilt University Medical Center, Division of Cardiovascular Medicine, 315 Medical Research Building II, Nashville, TN 37232-6300. E-mail mark.anderson{at}mcmail.vanderbilt.edu
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Abstract |
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Background—The ventricular arrhythmia torsade de pointes (TdP) occurs after QT interval prolongation and is associated with sudden cardiac death. The afterdepolarizations that initiate TdP are facilitated by protein kinase A and the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaM kinase).
Methods and Results—In this study, we evaluated the feasibility of suppression of TdP through systemic therapy with kinase inhibitory agents in an established animal model. Under control conditions, TdP was inducible in 6 of 8 rabbits. CaM kinase blockade with the calmodulin antagonist W-7 reduced TdP in a dose-dependent fashion (4 of 7 inducible at 25 µmol/kg and 1 of 7 inducible at 50 µmol/kg). Increased intracellular Ca2+ has been implicated in the genesis of afterdepolarizations, but pretreatment with high-dose W-7 did not prevent TdP in response to the L-type Ca2+ channel agonist BAY K 8644 (300 nmol/kg), suggesting that CaM kinase–independent activation of L-type Ca2+ current was not affected by W-7. Compared with control animals, W-7 reduced TdP inducibility without shortening the QT interval, increasing heart rate, or reducing the blood pressure. The protein kinase A antagonist H-8 also caused a dose-dependent reduction in TdP inducibility (5 of 6 at 1 µmol/kg, 4 of 6 at 5 µmol/kg, and 0 of 6 at 10 µmol/kg), but unlike W-7, H-8 did so by shortening the QT interval.
Conclusions—These findings show that the acute systemic application of W-7 and H-8 is hemodynamically tolerated and indicate that kinase inhibition may be a viable antiarrhythmic strategy.
Key Words: torsade de pointes • long-QT syndrome • calmodulin kinase
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Introduction |
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Drugs that prolong action potential (AP) repolarization can be antiarrhythmic through the lengthening of tissue refractoriness or the elimination of an excitable gap, thereby extinguishing reentry.1 AP prolongation also has proarrhythmic consequences by causing afterdepolarizations that trigger torsade de pointes (TdP) and that are associated with sudden death. An agent that could preserve the beneficial effects of AP prolongation without inducing afterdepolarizations and TdP thus is an important goal for antiarrhythmic drug development. Protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CaM kinase), and increased intracellular Ca2+ concentration ([Ca2+]i) have been implicated as causes of afterdepolarizations in isolated cardiac myocytes2 3 4 5 6 and isolated Langendorff-perfused heart models.7 PKA and CaM kinase both likely enhance the probability of afterdepolarizations by increasing [Ca2+]i, and the systemic administration of the sarcoplasmic reticulum (SR) Ca2+ uptake and release antagonists flunarizine8 and ryanodine8 9 prevents TdP. PKA and CaM kinase both act at L-type Ca2+ channels10 11 and SR Ca2+ stores12 13 14 to increase [Ca2+]i.
Afterdepolarizations are oscillations in cell membrane potential15 16 that are often associated with increased SR Ca2+ release and are suppressed by CaM kinase inhibition in isolated Langendorff-perfused hearts7 and cardiac myocytes.3 Recently, AP prolongation in response to the class III antiarrhythmic drug clofilium was shown to increase CaM kinase activity7 when afterdepolarizations were induced. The application of a CaM kinase inhibitor prevented the increase in CaM kinase activity without shortening AP duration.7 Afterdepolarizations are also associated with conditions favoring increased PKA activity,4 5 6 and ß-adrenergic receptor antagonists likely exert an antiarrhythmic action in long QT–related arrhythmias by decreasing PKA activity. Because of the known link among PKA, CaM kinase, and triggered arrhythmias, it is likely that inhibition of these kinases may prevent TdP. However, even the acute hemodynamic feasibility of the treatment of arrhythmias with systemically administered kinase inhibitory agents is unknown.
An ideal therapeutic kinase inhibitory agent would be
systemically bioavailable, cell membrane permeant, highly specific, and
potent and would not be associated with side effects. At the
present, no such inhibitors are thought to exist. W-7
[N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide] is a
water-soluble, cell membrane–permeant competitive
antagonist of calmodulin.17
W-7 IC50 values for
calmodulin-dependent enzymes range from 
25 to 50
µmol/L. Calmodulin is an ubiquitous intracellular
Ca2+-binding protein with a bilobed tertiary
structure containing 4 Ca2+-binding EF hand
domains.18 Calmodulin undergoes conformational
changes induced by Ca2+ binding that exposes the
activation site for calmodulin-dependent enzymes such as
CaM kinase. W-7 inhibits activation of calmodulin-dependent
enzymes by blocking access to this hydrophobic activation site
(Ki 12
µmol/L).18 W-7 is a less potent PKA or protein
kinase C (PKC) antagonist (Ki
110 µmol/L).19 20 H-8
[N-[2-methylamino)ethyl]-5-isoquinolinesulfonamide]
is a water-soluble, cell membrane–permeant derivative of W-7 with
enhanced inhibitory activity against a variety of protein
kinases, including protein kinase G
(Ki=0.5 µmol/L), PKA
(Ki=1.2 µmol/L), and PKC
(Ki=15 µmol/L), but without
appreciable activity against CaM kinase.17 These
agents were chosen for systemic use because of their high water
solubility and cell membrane permeability and their demonstrated
inhibitory efficacy in a wide range of mammalian
cells.17 In this study, the effects of these 2 kinase
inhibitors, administered systemically, were tested in an
established animal model of TdP.
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Methods |
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Rabbit Arrhythmia Model
The in vivo rabbit model of TdP was implemented as described by Carlsson et al21 with minor modifications. In brief, male New Zealand rabbits (weight 2.5 to 3.0 kg) were initially anesthetized with 35 mg/kg ketamine IM and 5 mg/kg xylazine IM. Supplemental xylazine (1 mg/kg IM) and ketamine (15 mg/kg IM) were administered 15 minutes after the initial doses to maintain adequate anesthesia (loss of withdrawal reflex) throughout the experiment. Rabbits were mechanically ventilated with room air (Harvard Rodent Ventilator), and the adjustment of respiratory parameters was guided by arterial blood gases (PO2 84 to 101 mm Hg, PCO2 33±0.6 mm Hg, pH 7.44±0.03). Arterial blood pressure was continuously monitored with a femoral artery cannula. A minimum 10-minute stabilization period was used before any further intervention. Methoxamine (70 nmol · kg-1 · min-1 IV) was then infused for 10 minutes before starting clofilium (100 nmol · kg-1 · min-1 IV), after which both agents were continued simultaneously for 30 minutes or until TdP induction. Animals were euthanized with 50 mg/kg pentobarbital IV after the study. All procedures performed in the present study were approved by the Vanderbilt University Animal Care Committee.
Systemic Application of Kinase Inhibitors
Control animals were infused with 5% dextrose solution (20 mL
total IV) at the same time as methoxamine infusion. The
experimental group animals were infused with 5% dextrose solution (20
mL total IV) containing the indicated concentration of W-7 or H-8 (both
from BIOMOL Research Laboratories) during methoxamine infusion.
A separate group of 4 rabbits were pretreated with 50 µmol/kg
W-7 and observed for 25 minutes without TdP after the
methoxamine and clofilium infusion, as described. Then, 1 mL of
the vehicle for the L-type Ca2+ channel agonist
BAY K 8644 was administered, which did not elicit TdP or any
hemodynamic changes. BAY K 8644 (300 nmol/kg IV bolus
in 1 mL polyethylene glycol/ethanol/saline [5:5:90 vol/vol]; BIOMOL
Research Laboratories) was then administered over 30 seconds, and the
animal was observed for 5 minutes.
ECG Recording
Standard surface ECG limb leads (I, II, III, aVF, aVL, and aVR)
and a midchest lead positioned at the sternal notch (V) were
continuously monitored and recorded at a paper speed of 100
mm/s (Electronics for Medicine, Honeywell Inc). ECG intervals were
analyzed with a digitizing tablet (Summagraphics Corp)
interfaced to a microcomputer. A 2-channel ECG was continuously
recorded on audiotape and analyzed with the use of an
ambulatory ECG monitoring system (Rozinn Electronics Inc).
TdP
TdP was defined as 
6 consecutive beats of polymorphic
ventricular tachycardia.
ECG Interval Measurements
ECG intervals were measured as the average from 3 consecutive
beats with a single lead providing the clearest end of the QT interval
(usually lead II or III).
QT Interval
QT interval measurements were recorded from the onset of the
QRS complex to the return of the T wave to the isoelectric line (Figure 1
). When present at >25% of the
amplitude of the T wave, the U wave was included in the QT duration
measurement.22
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Corrected QT Interval
The QT interval was corrected (QTc)
according to the method of Carlsson et al23 for
rabbits with the formula QTc=
QT-0.175(RR-300).
RR Interval
The RR interval was measured from the onset of consecutive QRS
complexes.
Chemicals
All chemicals were obtained from Sigma Chemical Co, unless
otherwise noted, and solutions were prepared fresh daily from
concentrated stock solutions.
Statistical Analysis
Mean±SD values was calculated for continuous variables, and
absolute and relative frequencies were measured for discrete
variables. Continuous variables were compared between groups
with the use of Student’s t test or 1-way ANOVA as
appropriate, and categorical variables were compared with the use
of Fisher’s exact test. Values of P
0.05 were considered
statistically significant.
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Results |
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Induction of TdP
After treatment with methoxamine and clofilium, a consistent sequential pattern of bradycardia, QT interval prolongation, and isolated premature ventricular contractions (PVCs) leading to long-short coupling intervals preceded TdP initiation (Figure 1A
). The time to the first PVC was
significantly increased in W-7–treated animals (19.0±8.0 minutes)
compared with control (7.7±5.9 minutes, P<0.01) or
H-8–treated (5.7±4.4 minutes, P<0.001) animals. TdP was
induced in 6 of 8 rabbits under control conditions (Figure 2).
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Prevention of TdP by W-7 and H-8
Both W-7 and H-8 prevented TdP inducibility in a
dose-dependent manner (Figure 2), consistent with the
reported roles of CaM kinase and PKA in the facilitation of
afterdepolarizations. TdP suppression was significant at 50
µmol/kg for W-7 and at 10 µmol/kg for H-8. TdP induction in
W-7–pretreated animals tended to occur later after the infusion of
methoxamine and clofilium than in controls. TdP was induced
with the L-type Ca2+ current agonist BAY K 8644
after W-7 (50 µmol/kg) pretreatment (n=4), suggesting that these
animals remained capable of developing TdP by a
calmodulin- and CaM kinase–independent pathway (Figure 3).
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QT Interval Not Affected by W-7
QT interval prolongation favors induction of TdP, so suppression
of TdP by kinase inhibitory agents could simply reflect QT
interval shortening.24 Marked QT and
QTc interval prolongation occurred after
treatment with methoxamine and clofilium, and this prolongation
was not affected by pretreatment with W-7 (Figures 1B and 4). Treatment with H-8 (10
µmol/kg) resulted in significant QT and QTc
interval shortening (Figure 4). Thus, suppression of TdP by W-7,
but not by H-8, was independent of QT interval prolongation.
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Prevention of TdP by W-7 Not Due to Increase in Heart Rate
Because inducibility of TdP is known to be favored at low heart
rates,25 one possible mechanism for TdP suppression could
be an increase in heart rate. The heart rate slowed during the course
of methoxamine and clofilium infusion but was not significantly
different from control rates in W-7 (50 µmol/kg)–treated
animals (Figure 5). In contrast, H-8
(10 µmol/kg) increased heart rate at all time points (Figure 5). The suppression of TdP by W-7, but not by H-8, was
independent of an effect on heart rate.
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Kinase Antagonist Therapy Was Acutely
Hemodynamically Tolerated
The infusion of W-7 or H-8 at levels adequate to suppress TdP was
not associated with a decrease in systolic (Figure 6A) or diastolic (Figure 6B) blood pressure. On the contrary, W-7–treated animals had a
tendency to increase both systolic and diastolic
blood pressure. Thus, the systemic administration of these kinase
inhibitory agents was acutely
hemodynamically tolerated in this animal model.
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Discussion |
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Serine/Threonine Kinases in Cardiovascular System
Because serine/threonine kinases are ubiquitous and regulate a diverse array of target proteins in the cardiovascular system, the consequences of the use of systemic kinase inhibitory agents are unknown. In the cardiovascular system, PKA and PKC are both known to affect heart rate,26 27 and PKA,28 29 PKC,30 31 32 33 protein kinase G,28 34 and CaM kinase10 13 14 35 36 37 all participate in the regulation of smooth and cardiac muscle [Ca2+]i. Thus, the acute hemodynamic response to the systemic application of these inhibitory agents could be an important limitation in the development of novel approaches to antiarrhythmic therapy with the use of serine/threonine kinase inhibitory agents. On the other hand, the inhibition of the cardiac cell membrane ionic currents and exchangers responsible for afterdepolarizations may be accomplished with sufficiently low concentrations of kinase inhibitory agents to avoid systemic toxicities. New approaches to drug development through the use of combinatorial chemistry may lead to agents with increased potency and specificity compared with currently available agents.38
Role of Serine/Threonine Kinases in Arrhythmias
Both PKA and CaM kinase are thought to have proarrhythmic actions
due to enhancement of L-type Ca2+
current.3 4 5 10 PKA has long been an "indirect"
antiarrhythmic drug target because clinically available ß-adrenergic
receptor antagonists prevent ß-agonist mediated increases
in PKA activity. These agents have been shown to reduce sudden cardiac
death39 and are used in patients with long QT
syndromes.25 In contrast to PKA, CaM kinase activity is
generally not attributable to the activation of a single receptor type
but rather increases in response to elevated
[Ca2+]i.40
CaM kinase activity increases during AP prolongation and
afterdepolarizations, and CaM kinase inhibition prevents
afterdepolarizations without shortening AP duration in isolated
hearts.7 Although cell membrane permeant kinase
inhibitors have long been available as pharmacological and
research tools,17 the ubiquitous nature of these kinases
has perhaps been viewed as a potential obstacle to systemic kinase
inhibition for therapy of cardiac arrhythmias. The findings
presented here suggest that at least for acute administration,
2 such agents are hemodynamically tolerated at
concentrations effective for the suppression of
arrhythmias.
Kinase Inhibitory Agents
Although a role of CaM kinase in the facilitation of
afterdepolarizations in isolated cells has been inferred with the use
of highly specific inhibitory peptides,2 3 no
cell membrane–permeable agents with similar specificity adequate for
systemic administration presently exist. Both W-7 and H-8 can act
at many different cellular targets by virtue of their broad kinase
inhibitory actions and because these agents may directly
inhibit nonenzyme proteins such as ion channels.7 10 41
The finding that systemic blood pressure increased after W-7
administration indicates that L-type Ca2+ current
inhibition was not a predominant action at the concentration used to
suppress TdP. Thus, a limitation of this study is that the suppression
of TdP cannot be definitively ascribed to CaM kinase or PKA inhibition.
However, the finding that TdP suppression did occur as predicted in
previous cellular and in vitro studies without untoward
hemodynamic consequences is an important step for the
demonstration of the feasibility of this novel approach to
antiarrhythmic therapy.
Prevention of TdP In Vivo
The suppression of TdP by both W-7 and H-8 occurred in a
dose-dependent manner. H-8 did not suppress TdP at concentrations
predicted to be selective for PKA inhibition, although the effective
intracellular concentration is unknown. At higher concentrations,
compatible with PKA and PKC inhibition, H-8 was effective in the
suppression of TdP. W-7 at concentrations predicted to inhibit
calmodulin-dependent processes, including those mediated by
CaM kinase, was also effective in the suppression of TdP. The findings
that PVC onset was delayed by W-7 suggests that CaM kinase inhibition
reduced the probability of a triggering event (ie, an
afterdepolarization). Our findings do not provide information regarding
possible affects of kinase inhibitors on the substrate for
arrhythmia maintenance (eg, dispersion of
repolarization). It will be important to better define the mechanisms
of action of kinase inhibitory agents in TdP prevention in
future studies through the measurement of afterdepolarizations and QT
interval dispersion. Although the rabbit TdP model of the present
study is highly reproducible and widely used, studies in other models,
and ultimately in humans, will be required to determine the potential
clinical use of kinase inhibition as a therapy for
arrhythmias.
Proarrhythmia and QT Interval Prolongation
The inhibition of TdP by W-7 was different from that seen
after treatment with H-8. The most striking difference was that W-7 did
not result in a decrease in QT interval, whereas H-8 treatment
significantly shortened the QT interval. QT interval shortening
suggests that effects other than kinase inhibition may be important for
TdP suppression with H-8. Alternately, inhibition of PKA (and perhaps
other kinases) with H-8 shortens the QT interval. The suppression of
TdP without shortening of the QT interval suggests that CaM kinase
inhibitory agents may allow separation of the beneficial
actions of QT prolongation (ie, increased inotropy and the class III
antiarrhythmic effect) from the proarrhythmic actions (ie,
afterdepolarizations and TdP). Although other mechanisms might be
operative, the data presented here raise the strong possibility
that direct targeting of intracellular kinases is feasible and produces
important antiarrhythmic actions.
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Acknowledgments |
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This work was supported by NIH grants HL-03727, HL-62494 (both to Dr Anderson), HL-46681, and HL-49989 (both to Dr Roden) and a Cardiac Arrhythmia Research and Education Foundation, Inc award (Dr Anderson). Dr Roden is the holder of the William Stokes Chair in Experimental Therapeutics, a gift of the Dai-ichi Corporation. Dr Mazur is supported in part by the Israeli Pacing Foundation.
Received April 8, 1999; revision received June 25, 1999; accepted July 13, 1999.
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 Y.-J. Qu, V. E. Bondarenko, C. Xie, S. Wang, M. S. Awayda, H. C. Strauss, and M. J. Morales W-7 modulates Kv4.3: pore block and Ca2+-calmodulin inhibition Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2364 - H2377. [Abstract] [Full Text] [PDF]
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 M. E. Anderson Multiple downstream proarrhythmic targets for calmodulin kinase II: Moving beyond an ion channel-centric focus Cardiovasc Res, March 1, 2007; 73(4): 657 - 666. [Abstract] [Full Text] [PDF]
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 H. L. Tan, A. Bardai, W. Shimizu, A. J. Moss, E. Schulze-Bahr, T. Noda, and A. A. M. Wilde Genotype-Specific Onset of Arrhythmias in Congenital Long-QT Syndrome: Possible Therapy Implications Circulation, November 14, 2006; 114(20): 2096 - 2103. [Abstract] [Full Text] [PDF]
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 M. B. Thomsen, P. G.A. Volders, J. D.M. Beekman, J. Matz, and M. A. Vos Beat-to-Beat Variability of Repolarization Determines Proarrhythmic Outcome in Dogs Susceptible to Drug-Induced Torsades de Pointes J. Am. Coll. Cardiol., September 19, 2006; 48(6): 1268 - 1276. [Abstract] [Full Text] [PDF]
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 A. Kijtawornrat, Y. Nishijima, B. M. Roche, B. W. Keene, and R. L. Hamlin Use of a Failing Rabbit Heart as a Model to Predict Torsadogenicity Toxicol. Sci., September 1, 2006; 93(1): 205 - 212. [Abstract] [Full Text] [PDF]
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M. Viitasalo, L. Oikarinen, H. Swan, K. A. Glatter, H. Vaananen, H. Fodstad, N. Chiamvimonvat, K. Kontula, L. Toivonen, and M. M. Scheinman Ratio of Late to Early T-Wave Peak Amplitude in 24-h Electrocardiographic Recordings as Indicator of Symptom History in Patients With Long-QT Syndrome Types 1 and 2 J. Am. Coll. Cardiol., January 3, 2006; 47(1): 112 - 120. [Abstract] [Full Text] [PDF]
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M. Viitasalo, L. Oikarinen, H. Swan, K. A. Glatter, H. Vaananen, H. Fodstad, N. Chiamvimonvat, K. Kontula, L. Toivonen, and M. M. Scheinman Ratio of Late to Early T-Wave Peak Amplitude in 24-h Electrocardiographic Recordings as Indicator of Symptom History in Patients With Long-QT Syndrome Types 1 and 2 J. Am. Coll. Cardiol., December 13, 2005; (2005) j.jacc.2005.07.068v1. [Abstract] [Full Text] [PDF]
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 M. E. Anderson The Fire From Within: The Biggest Ca2+ Channel Erupts and Dribbles Circ. Res., December 9, 2005; 97(12): 1213 - 1215. [Full Text] [PDF]
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 J. M. Colomer, M. Terasawa, and A. R. Means Targeted Expression of Calmodulin Increases Ventricular Cardiomyocyte Proliferation and Deoxyribonucleic Acid Synthesis during Mouse Development Endocrinology, March 1, 2004; 145(3): 1356 - 1366. [Abstract] [Full Text] [PDF]
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I. Dzhura, Y. Wu, R. J Colbran, J. D Corbin, J. R Balser, and M. E Anderson Cytoskeletal disrupting agents prevent calmodulin kinase, IQ domain and voltage-dependent facilitation of L-type Ca2+ channels J. Physiol., December 1, 2002; 545(2): 399 - 406. [Abstract] [Full Text] [PDF]
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Y. Wu, J. Temple, R. Zhang, I. Dzhura, W. Zhang, R. Trimble, D. M. Roden, R. Passier, E. N. Olson, R. J. Colbran, et al. Calmodulin Kinase II and Arrhythmias in a Mouse Model of Cardiac Hypertrophy Circulation, September 3, 2002; 106(10): 1288 - 1293. [Abstract] [Full Text] [PDF]
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J. Wu, J. Wu, and D. P. Zipes Early Afterdepolarizations, U Waves, and Torsades de Pointes Circulation, February 12, 2002; 105(6): 675 - 676. [Full Text] [PDF]
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T. D. Gbadebo, R. W. Trimble, M. S.C. Khoo, J. Temple, D. M. Roden, and M. E. Anderson Calmodulin Inhibitor W-7 Unmasks a Novel Electrocardiographic Parameter That Predicts Initiation of Torsade de Pointes Circulation, February 12, 2002; 105(6): 770 - 774. [Abstract] [Full Text] [PDF]
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 M. E. Anderson, A. Mazur, T. Yang, and D. M. Roden Potassium Current Antagonist Properties and Proarrhythmic Consequences of Quinolone Antibiotics J. Pharmacol. Exp. Ther., March 1, 2001; 296(3): 806 - 810. [Abstract] [Full Text]
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