© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Mechanisms of 
-adrenergic potentiation of ventricular arrhythmias in dogs with inherited arrhythmic sudden death
aDepartment of Pharmacology, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, New York, NY, USA
bDepartment of Clinical Sciences, College of Veterinary Medicine of Cornell University, Ithaca, NY, USA
cDepartment of Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY, USA
* Corresponding author. Department of Pharmacology, College of Physicians and Surgeons of Columbia University, 630 West 168 Street, PH 7West-321, New York, NY, 10032, USA. Tel.: +1-212-305-8754; fax: +1-212-305-8351. mrr1{at}columbia.edu
Objective: In German shepherd dogs having inherited arrhythmias and sudden death, pause-dependent arrhythmias are triggered by early afterdepolarizations (EADs) originating from left ventricular (LV) Purkinje fibers (PF). Heterogeneity of LV repolarization provides the arrhythmogenic substrate. To elucidate the mechanisms whereby 
-adrenergic stimulation exacerbates these arrhythmias we tested the effects of phenylephrine on both arrhythmogenic trigger and substrate. Methods and results: We used microelectrode techniques to record action potentials from LV and right ventricular (RV) PF and from midmyocardial sections of anteroseptal, anterobasal and posterobasal LV wall of unafflicted and afflicted dogs. EADs occurred spontaneously in 8 of 12 LV PF and in no RV PF from afflicted dogs and in no PF from unafflicted dogs. In LV PF from afflicted dogs, phenylephrine (10–9–10–5 M) concentration-dependently decreased membrane potential, induced abnormal automaticity at membrane potentials from –65 to –45 mV in 6 LV PF and potentiated EADs in another 6. To determine the mechanisms of membrane depolarization we studied phenylephrine effects on IK1 in voltage-clamped single LV and RV PF cells from afflicted dogs. In LV PF, phenylephrine (10–5 M) reduced IK1 over the range of –120 to –40 mV and had no effects on RV PF. Regional heterogeneity of LV repolarization was observed in afflicted dogs only. Phenylephrine had no effects on repolarization in either group. Conclusion(s): -adrenergic stimulation exacerbates arrhythmias in afflicted dogs by increasing the arrhythmogenic trigger while leaving the substrate unchanged. Decrease in IK1 contributes importantly to -adrenergic effects on LV PF.
KEYWORDS Arrhythmia; Sudden death; Ion channels
Time for primary review 20 days
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