This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mazur, A. Articles by Anderson, M. E. Search for Related Content PubMed PubMed Citation Articles by Mazur, A. Articles by Anderson, M. E.

(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

Alexander Mazur, MD; Dan M. Roden, MD; Mark E. Anderson, MD, PhD

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

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

This article has been cited by other articles:

				N. Gaur, Y. Rudy, and L. Hool Contributions of Ion Channel Currents to Ventricular Action Potential Changes and Induction of Early Afterdepolarizations During Acute Hypoxia Circ. Res., December 4, 2009; 105(12): 1196 - 1203. [Abstract] [Full Text] [PDF]

				C. M. Sag, D. P. Wadsack, S. Khabbazzadeh, M. Abesser, C. Grefe, K. Neumann, M.-K. Opiela, J. Backs, E. N. Olson, J. H. Brown, et al. Calcium/Calmodulin-Dependent Protein Kinase II Contributes to Cardiac Arrhythmogenesis in Heart Failure Circ Heart Fail, November 1, 2009; 2(6): 664 - 675. [Abstract] [Full Text] [PDF]

				X. Qi, Y.-H. Yeh, D. Chartier, L. Xiao, Y. Tsuji, B. J.J.M. Brundel, I. Kodama, and S. Nattel The Calcium/Calmodulin/Kinase System and Arrhythmogenic Afterdepolarizations in Bradycardia-Related Acquired Long-QT Syndrome Circ Arrhythm Electrophysiol, June 1, 2009; 2(3): 295 - 304. [Abstract] [Full Text] [PDF]

				V. Yarotskyy, G. Gao, B. Z. Peterson, and K. S. Elmslie The Timothy syndrome mutation of cardiac CaV1.2 (L-type) channels: multiple altered gating mechanisms and pharmacological restoration of inactivation J. Physiol., February 1, 2009; 587(3): 551 - 565. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]