Published online before print December 1, 2003, doi: 10.1161/01.CIR.0000101926.43759.10
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2003;108:3157-3163.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Pharmacological Modulation of Cardiac Gap Junctions to Enhance Cardiac Conduction
Evidence Supporting a Novel Target for Antiarrhythmic Therapy
From The Heart and Vascular Research Center and the Department of Biomedical Engineering, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio.
Correspondence to David S. Rosenbaum, MD, Director, Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Dr, Hamman 322, Cleveland, OH 44109-1998. E-mail drosenbaum{at}metrohealth.org
Received May 23, 2003; revision received August 8, 2003; accepted August 14, 2003.
Background— Disease-induced alterations of cardiac gap junctions lead to intercellular uncoupling, which is an important mechanism of arrhythmogenesis. Therefore, drugs that selectively open gap junctions potentially offer a novel strategy for antiarrhythmic therapy. Because the peptide ZP123 was found to increase conductance between paired myocytes, we hypothesized that ZP123 would suppress acidosis-induced gap junction closure in the intact heart.
Methods and Results— High-resolution optical mapping was used to measure conduction velocity (CV) and action potential duration from ventricular epicardium of Langendorff-perfused guinea pig hearts at baseline (pH 7.4) and during 45 minutes of perfusion with acidotic (pH 6.0) Tyrode’s solution with (n=8) and without (control, n=7) ZP123 (80 nmol/L). Acidosis produced conduction slowing transverse (29.1±0.1 to 16.8±0.2 cm/s, P<0.0001) and longitudinal (47.2±2.4 to 33.2±4.8 cm/s, P<0.0001) to cardiac fibers. Importantly, ZP123 inhibited conduction slowing during acidosis by approximately 60%. The peak effect of ZP123 was achieved after 16 minutes of acidosis, consistent with inhibition of uncoupling. ZP123 did not affect Na+ current in isolated myocytes, additionally affirming that preservation of CV was attributable to the compound’s action on gap junctions. ZP123 had no effect on CV in the absence of acidosis, suggesting that drug activity targets gap junctions under metabolic stress. Action potential duration heterogeneity was significantly reduced by ZP123 (6.7±0.8 ms) compared with controls (9.7±3.1 ms, P<0.05), presumably by enhancing cell-to-cell coupling.
Conclusions— These data suggest that ZP123 significantly attenuates gap junction closure during acidosis. Preservation of intercellular coupling diminished CV slowing and heterogeneous repolarization, eliminating arrhythmogenic substrates.
Key Words: electrophysiology • mapping • ischemia
This article has been cited by other articles:
 |
|
 |
|
  S.-M. Chaldoupi, P. Loh, R. N.W. Hauer, J. M.T. de Bakker, and H. V.M. van Rijen The role of connexin40 in atrial fibrillation Cardiovasc Res, October 1, 2009; 84(1): 15 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Verma, B. D. Larsen, W. Coombs, X. Lin, G. Spagnol, P. L. Sorgen, S. M. Taffet, and M. Delmar Novel Pharmacophores of Connexin43 Based on the "RXP" Series of Cx43-Binding Peptides Circ. Res., July 17, 2009; 105(2): 176 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hagen, A. Dietze, and S. Dhein Human cardiac gap-junction coupling: effects of antiarrhythmic peptide AAP10 Cardiovasc Res, July 15, 2009; 83(2): 405 - 415. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Laurent, H. Leong-Poi, I. Mangat, G. W. Moe, X. Hu, P. P.-S. So, E. Tarulli, A. Ramadeen, E. I. Rossman, J. K. Hennan, et al. Effects of Chronic Gap Junction Conduction-Enhancing Antiarrhythmic Peptide GAP-134 Administration on Experimental Atrial Fibrillation in Dogs Circ Arrhythm Electrophysiol, April 1, 2009; 2(2): 171 - 178. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Lewandowski, K. Procida, R. Vaidyanathan, W. Coombs, J. Jalife, M. S. Nielsen, S. M. Taffet, and M. Delmar RXP-E: A Connexin43-Binding Peptide That Prevents Action Potential Propagation Block Circ. Res., August 29, 2008; 103(5): 519 - 526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Lin, C. Zemlin, J. K. Hennan, J. S. Petersen, and R. D. Veenstra Enhancement of ventricular gap-junction coupling by rotigaptide Cardiovasc Res, August 1, 2008; 79(3): 416 - 426. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Ehrlich, P. Biliczki, S. H. Hohnloser, and S. Nattel Atrial-Selective Approaches for the Treatment of Atrial Fibrillation J. Am. Coll. Cardiol., February 26, 2008; 51(8): 787 - 792. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Wit and H. S. Duffy Drug development for treatment of cardiac arrhythmias: targeting the gap junctions Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H16 - H18. [Full Text] [PDF]
|
|
|
|
|
|
A. L. Kjolbye, M. Dikshteyn, B. C. Eloff, I. Deschenes, and D. S. Rosenbaum Maintenance of intercellular coupling by the antiarrhythmic peptide rotigaptide suppresses arrhythmogenic discordant alternans Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H41 - H49. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-q. Zhong, G. Laurent, P. P.-S. So, Xudong Hu, J. K. Hennan, and P. Dorian Effects of Rotigaptide, a Gap Junction Modifier, on Defibrillation Energy and Resuscitation From Cardiac Arrest in Rabbits Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2007; 12(1): 69 - 77. [Abstract] [PDF]
|
|
|
|
 |
|
 J. M. Guerra, T. H. Everett IV, K. W. Lee, E. Wilson, and J. E. Olgin Effects of the Gap Junction Modifier Rotigaptide (ZP123) on Atrial Conduction and Vulnerability to Atrial Fibrillation Circulation, July 11, 2006; 114(2): 110 - 118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Shibayama, R. Lewandowski, F. Kieken, W. Coombs, S. Shah, P. L. Sorgen, S. M. Taffet, and M. Delmar Identification of a Novel Peptide That Interferes With the Chemical Regulation of Connexin43 Circ. Res., June 9, 2006; 98(11): 1365 - 1372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Hennan, R. E. Swillo, G. A. Morgan, J. C. Keith Jr., R. G. Schaub, R. P. Smith, H. S. Feldman, K. Haugan, J. Kantrowitz, P. J. Wang, et al. Rotigaptide (ZP123) Prevents Spontaneous Ventricular Arrhythmias and Reduces Infarct Size During Myocardial Ischemia/Reperfusion Injury in Open-Chest Dogs J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 236 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Li, V. V. Patel, and G. L. Radice Dysregulation of cell adhesion proteins and cardiac arrhythmogenesis. Clin. Med. Res., March 1, 2006; 4(1): 42 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. R. Jorgensen, S. C. Teilmann, Z. Henriksen, E. Meier, S. S. Hansen, J.-E. B. Jensen, O. H. Sorensen, and J. S. Petersen The Antiarrhythmic Peptide Analog Rotigaptide (ZP123) Stimulates Gap Junction Intercellular Communication in Human Osteoblasts and Prevents Decrease in Femoral Trabecular Bone Strength in Ovariectomized Rats Endocrinology, November 1, 2005; 146(11): 4745 - 4754. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Xing, A. L. Kjolbye, J. S. Petersen, and J. B. Martins Pharmacological stimulation of cardiac gap junction coupling does not affect ischemia-induced focal ventricular tachycardia or triggered activity in dogs Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H511 - H516. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Poelzing and D. S. Rosenbaum Altered connexin43 expression produces arrhythmia substrate in heart failure Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1762 - H1770. [Abstract] [Full Text] [PDF]
|
|