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Articles in PresS, published online ahead of print November 8, 2001
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00700.2001
Submitted on August 7, 2001
Accepted on October 15, 2001
1 Medicine, Northwestern University Medical School, Chicago, IL, USA
* To whom correspondence should be addressed. E-mail: ja-wasserstrom{at}northwestern.edu.
The purpose of this study was to investigate the effects of cardiac glycosides on single channel activity of the cardiac sarcoplasmic reticulum Ca2+ release channel (or ryanodine receptors, RyR2 channels) and how this action might contribute to their inotropic and/or toxic actions. Heavy SR vesicles isolated from dog left ventricle were fused with artificial planar lipid bilayers in order to measure single RyR2 channel activity. Digoxin and actodigin increased single channel activity at low concentrations normally associated with therapeutic plasma levels, yielding an EC50 of about 0.2nM for each agent. Channel activation by glycosides did not require MgATP and occurred only when digoxin was applied to the cytoplasmic side of the channel. Similar results were obtained in human RyR2 channels; however neither the crude skeletal nor the purified cardiac channel was activated by glycosides. Channel activation was dependent upon [Ca2+] on the lumenal side of the bilayer with maximal stimulation occurring between 0.3-10mM. Rat RyR2 channels were activated by digoxin only at 1µM, consistent with the lower sensitivity to glycosides in rat heart. These results suggest a model in which RyR2 channel activation by digoxin occurs only when lumenal [Ca2+] was increased above 300µM (in the physiological range). Consequently, increasing SR load (by Na+ pump inhibition) serves to amplify SR release by promoting direct RyR2 channel activation via a lumenal Ca2+-sensitive mechanism. This high affinity effect of glycosides could contribute to increased SR Ca2+ release and might play a role in the inotropic and/or toxic actions of glycosides in vivo.
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