Role of Calcium Loading in Early Afterdepolarizations Generated by Cs+ in Canine and Guinea Pig Purkinje Fibers

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Abstract
Our previous observations indicate that the Na+:Ca2+ exchange current (INa:Ca) plays an important role in early afterdepolarizations occurring at more negative Vm (L-EAD). The purpose of these studies was to examine the role of Ca(2+)-loading, which stimulates INa:Ca, in generation of L-EAD. Purkinje strands and preparations of ventricular myocardium from dogs and guinea pigs were superfused with oxygenated physiologic buffer solutions at 37 degrees C. To induce EADs, [K+]o was reduced to 2.0 to 3.0 mM and [Cs+]o (3.6 to 4.0 mM) was added at slow rates of < or = 0.3 Hz. Isometric contraction in canine Purkinje strands and guinea pig papillary muscles doubled in 1-hour exposure to Cs+ and low [K+]o at slow rates and the uptake of 45Ca2+ was approximately doubled after 30 minutes. Forty-three percent of Purkinje fibers developed L-EAD after a latent period of 17 to 123 minutes of exposure. Ouabain (0.2 microM) suppressed L-EAD within 10 minutes reversibly. Ca(2+)-loading (low [Na+]o or high [Ca2+]o) for 5 to 10 minutes before exposure to Cs+, low [K+]o, and slow rates resulted in rapid development of L-EAD in all preparations during subsequent exposure. In Ca(2+)-loaded preparations, delayed afterdepolarizations (DADs) as well as L-EADs developed. Reduction of K+ currents with Cs+, low [K+]o, and slow rates induced L-EAD in a fraction of Purkinje fibers after a latent period during which Ca(2+)-loading of the sarcoplasmic reticulum occurred, while fibers preloaded with Ca2+ developed L-EAD rapidly and uniformly. These findings indicate that Ca(2+)-loading is a critical condition for the development of L-EAD. Early suppression of L-EAD by ouabian suggests a dependence of L-EAD on low [Na+]i. These findings implicate INa:Ca in the generation of L-EAD.