Combined potassium and calcium channel blocking activities as a basis for antiarrhythmic efficacy with low proarrhythmic risk: experimental profile of BRL-32872

A Bril, B Gout, M Bonhomme, L Landais, JF Faivre, P Linee, RH Poyser and RR Ruffolo

SmithKline Beecham Laboratories Pharmaceutiques, Saint-Gregoire, France.

In the search for novel antiarrhythmic agents, compounds with a diversity of electrophysiological actions have been suggested to result in treatments with potentially improved efficacy but with reduced proarrhythmic risk. To test this hypothesis, the antiarrhythmic versus proarrhythmic profile of BRL-32872, a novel agent with combined potassium and calcium channel blocking activity, was assessed in two different in vivo models of ventricular arrhythmia. Furthermore, the effects of potassium and calcium channel antagonists given either alone or in combination were assessed in the same models. Dogs with myocardial infarction received intravenously either vehicle, BRL-32872, the class III antiarrhythmic agent, E-4031, verapamil or a combination of E-4031 with verapamil (n = 8 per group). Ventricular tachyarrhythmias were induced by programmed electrical stimulation (PES). BRL-32872 (0.1, 0.3, 1.0 mg/kg) significantly increased QTc interval (from 387 +/- 10 to 462 +/- 19 msec.sec-1/2 at 1.0 mg/kg, P < .01). Ventricular effective refractory periods were increased in normal and infarcted areas (P < .01). Similar effects were observed with E- 4031 (0.1, 0.3, 1.0 mg/kg). Verapamil (0.03, 0.1, 0.3 mg/kg) reduced heart rate, mean arterial pressure and, to a lesser extent, (+)dP/dtmax. Verapamil did not change QTc interval and ventricular effective refractory periods, but increased PR interval (P < .001). PES- induced tachyarrhythmias were not changed by vehicle or increasing doses of verapamil. E-4031 reduced the severity of arrhythmias from sustained ventricular tachycardia (VT) to nonsustained VT (7 dogs at 1.0 mg/kg, P = .013 vs. vehicle). BRL-32872 (0.1 and 0.3 mg/kg) suppressed the induction of sustained VT in six dogs (P = .02 vs. vehicle). In the presence of BRL-32872, 1.0 mg/kg, five dogs became noninducible to PES (P = .013 vs. vehicle). Combination of E-4031 (0.1 mg/kg) with verapamil provided a degree of protection that was similar to that observed with BRL-32872. In a second model, the proarrhythmic potential of BRL-32872 was assessed in anesthetized rabbits sensitized to develop torsades de pointes (TdP). BRL-32872 was compared with the class III antiarrhythmic agents, E-4031, dofetilide, clofilium and RP- 58866. The pure class III antiarrhythmic agents induced TdP in 50 to 90% of the rabbits, and prolonged QT interval by 20 to 50%. BRL-32872 (10 micrograms/kg/min) increased QT interval by 35 +/- 5%, but did not promote TdP. In additional experiments, verapamil reduced the incidence of TdP induced by E-4031. These results show that BRL-32872 is a potent antiarrhythmic compound in a model of PES-induced arrhythmias and induces fewer proarrhythmic events than typical class III antiarrhythmic agents. The effects observed with BRL-32872 suggest that a compound with a combination of potassium (class III) and calcium (class IV) channel antagonistic properties might constitute a novel antiarrhythmic agent with reduced proarrhythmic risk.

Volume 276, Issue 2, pp. 637-646, 02/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				K. S. Dujardin, B. Dumotier, M. David, M. Guizy, C. Valenzuela, and L. M. Hondeghem Ultrafast sodium channel block by dietary fish oil prevents dofetilide-induced ventricular arrhythmias in rabbit hearts Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1414 - H1421. [Abstract] [Full Text] [PDF]

				N. Hashimoto, T. Yamashita, N. Fujikura, and N. Tsuruzoe NIP-141, a multiple ion channel blocker, terminates aconitine-induced atrial fibrillation and prevents the rapid pacing-induced atrial effective refractory period shortening in dogs Europace, April 1, 2007; 9(4): 246 - 251. [Abstract] [Full Text] [PDF]

				P. M.R. Orth, J. C. Hesketh, C. K.H. Mak, Y. Yang, S. Lin, G. N. Beatch, A. M. Ezrin, and D. Fedida RSD1235 blocks late INa and suppresses early afterdepolarizations and torsades de pointes induced by class III agents Cardiovasc Res, June 1, 2006; 70(3): 486 - 496. [Abstract] [Full Text] [PDF]

				G. A. Gintant, Z. Su, R. L. Martin, and B. F. Cox Utility of hERG Assays as Surrogate Markers of Delayed Cardiac Repolarization and QT Safety Toxicol Pathol, January 1, 2006; 34(1): 81 - 90. [Abstract] [Full Text] [PDF]

				C. Antzelevitch, L. Belardinelli, L. Wu, H. Fraser, A. C. Zygmunt, A. Burashnikov, J. M. Di Diego, J. M. Fish, J. M. Cordeiro, R. J. Goodrow Jr, et al. Electrophysiologic Properties and Antiarrhythmic Actions of a Novel Antianginal Agent Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2004; 9(1_suppl): S65 - S83. [Abstract] [PDF]

				D. Thomas, B. Gut, G. Wendt-Nordahl, and J. Kiehn The Antidepressant Drug Fluoxetine Is an Inhibitor of Human Ether-A-Go-Go-Related Gene (HERG) Potassium Channels J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 543 - 548. [Abstract] [Full Text] [PDF]

				L. Carlsson Drug-induced torsade de pointes: the perspectives of industry Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K114 - K120. [Abstract] [PDF]

				D. Thomas, G. Wendt-Nordahl, K. Röckl, E. Ficker, A. M. Brown, and J. Kiehn High-Affinity Blockade of Human Ether-A-Go-Go-Related Gene Human Cardiac Potassium Channels by the Novel Antiarrhythmic Drug BRL-32872 J. Pharmacol. Exp. Ther., April 12, 2001; 297(2): 753 - 761. [Abstract] [Full Text]

				S. C. Verduyn, J. M. v. Opstal, J. D. Leunissen, and M. A. Vos Assessment of the Pro-Arrhythmic Potential of Anti-Arrhythmic Drugs: An Experimental Approach Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2001; 6(1): 89 - 97. [PDF]

				R. R. Brooks, A. P. Drexler, A. E. Maynard, H. Al-Khalidi, and D. R. Kostreva Proarrhythmia of Azimilide and Other Class III Antiarrhythmic Agents in the Adrenergically Stimulated Rabbit Experimental Biology and Medicine, February 1, 2000; 223(2): 183 - 189. [Abstract] [Full Text]

				S. Zhang, Z. Zhou, Q. Gong, J. C. Makielski, and C. T. January Mechanism of Block and Identification of the Verapamil Binding Domain to HERG Potassium Channels Circ. Res., May 14, 1999; 84(9): 989 - 998. [Abstract] [Full Text] [PDF]

				A. Bril, M.-C. Forest, B. Cheval, and J.-F. Faivre Combined potassium and calcium channel antagonistic activities as a basis for neutral frequency dependent increase in action potential duration: comparison between BRL-32872 and azimilide Cardiovasc Res, January 1, 1998; 37(1): 130 - 140. [Abstract] [Full Text] [PDF]