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(Circulation. 1997;96:1275-1281.)
© 1997 American Heart Association, Inc.

Articles

Withdrawal of Acetylcholine Elicits Ca²⁺-Induced Delayed Afterdepolarizations in Cat Atrial Myocytes

Y.G. Wang, MD; J. Hüser, PhD; L.A. Blatter, MD, Dr med; ; S.L. Lipsius, PhD

From Loyola University of Chicago, Stritch School of Medicine, Department of Physiology, Maywood, Ill.

Correspondence to Stephen L. Lipsius, PhD, Department of Physiology, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153. E-mail slipsiu{at}wpo.it.luc.edu

Background Recent experiments in atrial myocytes indicate that withdrawal of cholinergic agonist can directly increase Ca²⁺ influx via L-type Ca²⁺ current and stimulate Ca²⁺ uptake into the sarcoplasmic reticulum (SR), thereby increasing intracellular Ca²⁺. Overload of cellular Ca²⁺ within the SR can initiate various types of atrial dysrhythmias. The present study was designed to determine whether withdrawal of acetylcholine (ACh) can elicit Ca²⁺-induced delayed afterdepolarizations (DADs) in atrial myocytes.

Methods and Results A nystatin perforated-patch whole-cell method and fluorescence microscopy (indo 1) were used to measure electrical activities and intracellular free Ca²⁺ ([Ca²⁺]_i), respectively. Withdrawal of ACh (1 µmol/L) increased action potential duration, shifted plateau voltage toward positive, and generated DADs that initiated spontaneous action potentials. Voltage-clamp analysis revealed that withdrawal of ACh elicited a rebound stimulation of L-type Ca²⁺ current (I_Ca,L) (+45%) and Na/Ca exchange current (I_NaCa) (+16%) and the appearance of transient inward current (I_ti) and spontaneous [Ca²⁺]_i transients. Each of these changes induced by withdrawal of ACh was abolished by Rp-cAMPs (50 to 100 µmol/L) or H-89 (2 µmol/L), inhibitors of cAMP-dependent protein kinase A. Ryanodine (1 µmol/L) abolished I_NaCa and the appearance of I_ti without decreasing the rebound stimulation of I_Ca,L elicited by withdrawal of ACh.

Conclusions Withdrawal of ACh can elicit cAMP-mediated stimulation of Ca²⁺ influx via I_Ca,L and uptake of SR Ca²⁺. As a result, cellular Ca²⁺ overload causes enhanced SR Ca²⁺ release and the initiation of DADs. These mechanisms may generate triggered and/or spontaneous atrial depolarizations elicited by withdrawal of vagal nerve activity.

Key Words: arrhythmia • electrophysiology • action potentials • calcium • adenosine

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