© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Differential efficacy of L- and T-type calcium channel blockers in preventing tachycardia-induced atrial remodeling in dogs
aDepartment of Medicine, University of Montreal, Research Center, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8
bHoffman-La Roche Pharmaceuticals, Basel, Switzerland
cDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Canada
* Corresponding author. Tel.: +1-514-376-3330; fax: +1-514-376-1355 nattel{at}icm.umontreal.ca
Background: Tachycardia-induced remodeling likely plays an important role in atrial fibrillation (AF) maintenance and recurrence after cardioversion, and Ca2+ overload may be an important mediator. This study was designed to evaluate the relative efficacies of selective T-type (mibefradil) and L-type (diltiazem) Ca2+-channel blockers in preventing tachycardia-induced atrial remodeling. Methods: Dogs were given daily doses of mibefradil (100 mg), diltiazem (240 mg) or placebo in a blinded fashion, beginning 4 days before and continuing through a 7-day period of atrial pacing at 400 bpm. An electrophysiological study was then performed to assess changes in refractoriness, refractoriness heterogeneity and AF duration. Results: Mean duration of burst-pacing induced AF was similar in placebo (567±203 s) and diltiazem-treated (963±280 s, P = NS) animals, but was much less in mibefradil-treated dogs (3.6±0.9 s, P<0.002) and non-paced controls (6.6±2.7 s). In contrast to mibefradil, diltiazem did not alter tachycardia-induced refractoriness abbreviation or heterogeneity. To exclude inadequate dosing as an explanation for diltiazem's inefficacy, we studied an additional group of dogs treated with 720 mg/day of diltiazem, and again noted no protective effect. Acute intravenous administration of diltiazem to control dogs failed to alter atrial refractoriness or AF duration, excluding a masking of remodeling suppression by offsetting profibrillatory effects of the drug. Conclusions: Whereas the selective T-type Ca2+-channel blocker mibefradil protects against atrial remodeling caused by 7-day atrial tachycardia, the selective L-type blocker diltiazem is without effect. These findings are potentially important for understanding the mechanisms and prevention of clinically-relevant atrial-tachycardia-induced remodeling.
KEYWORDS Antiarrhythmic agents; Arrhythmia (mechanisms); Ca-channel; Supraventr. arrhythmia
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Sun, D. Varela, D. Chartier, P. C. Ruben, S. Nattel, G. W. Zamponi, and N. Leblanc Differential Interactions of Na+ Channel Toxins with T-type Ca2+ Channels J. Gen. Physiol., July 1, 2008; 132(1): 101 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nattel, A. Maguy, S. Le Bouter, and Y.-H. Yeh Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial Fibrillation Physiol Rev, April 1, 2007; 87(2): 425 - 456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. S. Freeze, M. M. McNulty, and D. A. Hanck State-Dependent Verapamil Block of the Cloned Human Cav3.1 T-Type Ca2+ Channel Mol. Pharmacol., August 1, 2006; 70(2): 718 - 726. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Shiroshita-Takeshita, B. J.J.M. Brundel, J. Lavoie, and S. Nattel Prednisone prevents atrial fibrillation promotion by atrial tachycardia remodeling in dogs Cardiovasc Res, March 1, 2006; 69(4): 865 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Laleve, M. C. Rebsamen, S. Barrere-Lemaire, E. Perrier, J. Nargeot, J.-P. Benitah, and M. F. Rossier Aldosterone increases T-type calcium channel expression and in vitro beating frequency in neonatal rat cardiomyocytes Cardiovasc Res, August 1, 2005; 67(2): 216 - 224. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Pastukh, S. Wu, C. Ricci, M. Mozaffari, and S. Schaffer Reversal of hyperglycemic preconditioning by angiotensin II: role of calcium transport Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1965 - H1975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Caballero, R. Gomez, L. Nunez, I. Moreno, J. Tamargo, and E. Delpon Diltiazem inhibits hKv1.5 and Kv4.3 currents at therapeutic concentrations Cardiovasc Res, December 1, 2004; 64(3): 457 - 466. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Shiroshita-Takeshita, G. Schram, J. Lavoie, and S. Nattel Effect of Simvastatin and Antioxidant Vitamins on Atrial Fibrillation Promotion by Atrial-Tachycardia Remodeling in Dogs Circulation, October 19, 2004; 110(16): 2313 - 2319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. L. L'Allier, A. Ducharme, P.-F. Keller, H. Yu, M.-C. Guertin, and J.-C. Tardif Angiotensin-converting enzyme inhibition in hypertensive patients is associated with a reduction in the occurrence of atrial fibrillation J. Am. Coll. Cardiol., July 7, 2004; 44(1): 159 - 164. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kumagai, H. Nakashima, H. Urata, N. Gondo, K. Arakawa, and K. Saku Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2197 - 2204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Shinagawa, A. Shiroshita-Takeshita, G. Schram, and S. Nattel Effects of Antiarrhythmic Drugs on Fibrillation in the Remodeled Atrium: Insights Into the Mechanism of the Superior Efficacy of Amiodarone Circulation, March 18, 2003; 107(10): 1440 - 1446. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Perez-Reyes Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels Physiol Rev, January 1, 2003; 83(1): 117 - 161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Zachary, S. A. Hartleben, L. A. Frizzell, and W. D. O'Brien Jr Arrhythmias in Rat Hearts Exposed to Pulsed Ultrasound After Intravenous Injection of a Contrast Agent J. Ultrasound Med., December 1, 2002; 21(12): 1347 - 1356. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Sticherling, H. Tada, W. Hsu, A. C. Bares, H. Oral, F. Pelosi, B. P. Knight, S. A. Strickberger, and F. Morady Effects of Diltiazem and Esmolol on Cycle Length and Spontaneous Conversion of Atrial Fibrillation Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2002; 7(2): 81 - 88. [Abstract] [PDF]
|
|
|
|
|
|
S. Nattel, M. Allessie, and M. Haissaguerre Spotlight on atrial fibrillation--the 'complete arrhythmia' Cardiovasc Res, May 1, 2002; 54(2): 197 - 203. [Full Text] [PDF]
|
|
|
|
|
|
R. F Bosch and S. Nattel Cellular electrophysiology of atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 259 - 269. [Full Text] [PDF]
|
|
|
|
|
|
S. Nattel Therapeutic implications of atrial fibrillation mechanisms: can mechanistic insights be used to improve AF management? Cardiovasc Res, May 1, 2002; 54(2): 347 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Shinagawa, H. Mitamura, S. Ogawa, and S. Nattel Effects of inhibiting Na+/H+-exchange or angiotensin converting enzyme on atrial tachycardia-induced remodeling Cardiovasc Res, May 1, 2002; 54(2): 438 - 446. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kurita, H. Mitamura, A. Shiroshita-Takeshita, A. Yamane, M. Ieda, O. Kinebuchi, T. Sato, S. Miyoshi, M. Hara, S. Takatsuki, et al. Daily oral verapamil before but not after rapid atrial excitation prevents electrical remodeling Cardiovasc Res, May 1, 2002; 54(2): 447 - 455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. L.J.L. Thijssen, J. Ausma, and M. Borgers Structural remodelling during chronic atrial fibrillation: act of programmed cell survival Cardiovasc Res, October 1, 2001; 52(1): 14 - 24. [Abstract] [Full Text] [PDF]
|
|