The Journal of General Physiology
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The Journal of General Physiology, Vol 64, 320-342, Copyright © 1974 by The Rockefeller University Press

ARTICLE

Mode of Action of Chronotropic Agents in Cardiac Purkinje Fibers

Does Epinephrine Act by Directly Modifying the External Surface Charge?



Richard W. Tsien 1

1 From the Department of Physiology, Yale University School of Medicine, New Haven, Connecticut 06510

Hauswirth et al. (1968) proposed that epinephrine acts on iKK2 by adding its own positive charge to the external membrane surface near the iKK2 channel. This hypothesis was tested by using noncationic compounds, theophylline and R07-2956, which mimicked epinephrine's effects on pacemaker activity and on iKK2. In maximally effective doses, theophylline or R07-2956 occluded the effect of epinephrine, indicating a shared final common mechanism. Since theophylline and R07-2956 are noncationic at pH 7.4, the common mechanism cannot be a direct change in external surface charge. On the contrary, epinephrine does not interfere with the voltage shift produced by La+++, which is thought to modify the external surface charge. The results argue against the original hypothesis but leave open the possibility that an alteration in internal surface charge generates the observed voltage shift. The potency of theophylline and R07-2956 as phosphodiesterase inhibitors suggests that the final common mechanism begins with the elevation of intracellular cyclic AMP, leading to a saturable process which limits the voltage shift's magnitude. This hypothesis is used to generate dose-response curves describing the combined effects of epinephrine and theophylline, and these are compared with experimental data.

Submitted on February 14, 1974


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