Abstract
This study tested the hypothesis that combination ion channel blockers of the transient outward current (Ito) and the rapid component of the delayed rectifying current (IKr) would produce greater prolongation of the ventricular action potential duration (APD) and increased dispersion of the APD in hypertrophied hearts compared with control hearts. Isolated rabbit hearts were studied 48 ± 5 days postabdominal aortic banding. Left ventricular endocardial and epicardial APDs were significantly greater at baseline in the hypertrophied group than in controls (P < .05). The magnitude of APD prolongation induced by the Ito blocker 4-aminopyridine (4-AP) and combination 4-AP and the IKr blocker dofetilide was greater in the hypertrophied hearts than in the normal hearts (P < .01). Mean APD dispersion was significantly greater in the hypertrophied group than in the control hearts at baseline (P < .05). 4-AP increased APD dispersion by a similar magnitude in the hypertrophied hearts (10 ± 10 ms) and the control hearts (8 ± 8 ms, P= NS), whereas the combination 4-AP and dofetilide increased APD dispersion by a greater magnitude in the hypertrophied hearts (41 ± 28 ms) than the control hearts (21 ± 11 ms,P < .05). Ventricular fibrillation occurred spontaneously in four hypertrophied hearts (40%) during combination drug perfusion and in none of the control hearts (P< .05). Thus, combination Ito andIKr blockers cause greater prolongation APD and increased APD dispersion in left ventricular hypertrophy, and this is associated with the development of ventricular fibrillation.
Footnotes
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Send reprint requests to: Anne M. Gillis, M.D., FRCPC, Division of Cardiology, The University of Calgary, 3330 Hospital Dr., N.W., Calgary, Alberta, Canada T2N 4N1. E-mail:amgillis{at}ucalgary.ca
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↵1 This study was supported by the Medical Research Council of Canada. Dr. Gillis is a senior scholar of the Alberta Heritage Foundation for Medical Research.
- Abbreviations:
- APD
- action potential duration
- 4-AP
- 4-aminopyridine
- APD90
- action potential duration at 90% repolarization
- APDepi
- epicardial action potential duration
- APDendo
- endocardial action potential duration
- Ito transient outward current
- IKr, rapid component of the delayed rectifying current
- IK1
- inward rectifying current
- Received July 7, 1999.
- Accepted October 5, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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