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Ethacizin blockade of calcium channels: a test of the guarded receptor hypothesis
C F Starmer1, A I Undrovinas, F Scamps
1Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Abstract:
The effect on calcium channels of the sodium channel antagonist, ethacizin, was studied in isolated frog ventricular cells using the whole cell voltage-clamp methodology. Ethacizin was found to block inward calcium current in a frequency-, voltage-, and concentration-dependent manner. The frequency-dependent blocking properties were modeled by considering the drug interaction with a voltage-dependent mixture of calcium channels harboring either an accessible or an inaccessible binding site. With repetitive stimulation, the pulse-to-pulse reduction in peak current is shown to be exponential, with a rate linearly related to the interstimulus interval and the drug concentration. Observed frequency- and concentration-dependent blocks were consistent with the predictions of the model, and mixture-specific rate constants were estimated from these data. The negligible shift in channel inactivation and the reduction of apparent binding and unbinding rates with more polarized membrane potentials imply the active moiety of ethacizin blocks open channels and is trapped within the channel at resting membrane potentials. The binding rate at 0 mV is similar to that observed in studies of interactions of other open channel blocking agents with voltage- and ligand-gated channels.
Insights
Ethacizin, a sodium channel antagonist, blocks calcium channels in frog heart cells. This block is dependent on stimulation frequency, voltage, and drug concentration, suggesting a specific blocking mechanism.
Area of Science:
- Cardiovascular Pharmacology
- Ion Channel Physiology
Background:
- Sodium channel antagonists can exhibit off-target effects on other ion channels.
- Calcium channels play a critical role in cardiac contractility.
Purpose of the Study:
- To investigate the effects of ethacizin, a sodium channel antagonist, on calcium channels in frog ventricular cells.
- To elucidate the mechanism of ethacizin's interaction with calcium channels.
Main Methods:
- Whole-cell voltage-clamp technique applied to isolated frog ventricular cells.
- Analysis of inward calcium currents under varying stimulation frequencies, voltages, and ethacizin concentrations.
Main Results:
- Ethacizin demonstrated frequency-, voltage-, and concentration-dependent blockade of inward calcium current.
- A model of drug interaction with a voltage-dependent mixture of calcium channels accurately predicted observed blocking properties.
- Ethacizin appears to block open calcium channels and becomes trapped at resting potentials.
Conclusions:
- Ethacizin exhibits significant effects on cardiac calcium channels, independent of its primary action on sodium channels.
- The drug's interaction with calcium channels involves binding to open states and trapping at specific potentials.
- Findings provide insights into the complex pharmacology of ethacizin and ion channel interactions.