Mechanisms of alpha-adrenergic potentiation of ventricular arrhythmias in dogs with inherited arrhythmic sudden death.
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 alpha-adrenergic stimulation exacerbates these arrhythmias we tested the effects of phenylephrine on both arrhythmogenic trigger and substrate.


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.


CONCLUSIONS
Alpha-adrenergic stimulation exacerbates arrhythmias in afflicted dogs by increasing the arrhythmogenic trigger while leaving the substrate unchanged. Decrease in IK1 contributes importantly to alpha-adrenergic effects on LV PF.
Department of Pharmacology, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Eugene A
EA
Sosunov
Maria N
MN
Obreztchikova
Evgeny P
EP
Anyukhovsky
N Sydney
NS
Moïse
Peter
P
Danilo
Richard B
RB
Robinson
Michael R
MR
Rosen
D000200:Action Potentials / Q000187:drug effects; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000662:veterinary*; D003645:Death, Sudden / Q000209:etiology / Q000662:veterinary*; D004283:Dog Diseases / Q000378:metabolism*; D004285:Dogs; D006352:Heart Ventricles; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010656:Phenylephrine / Q000494:pharmacology*; D011690:Purkinje Fibers
D000316:Adrenergic alpha-Agonists; D010656:Phenylephrine