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The modulated receptor hypothesis revisited from the viewpoint of myocardial interstitial potential
1First Department of Internal Medicine, Kyushu University.
Abstract:
Time- and voltage-dependent interaction of antiarrhythmic agents with target cardiac ion channels is termed the modulated receptor hypothesis. Actually class I agents suppress the maximum upstroke rate (Vmax) of intracellular potential (Vic) depending on the pacing cycle length (PCL) and external potassium concentration ([K+]e). We examined this concept from the aspect of interstitial potential (Vis), since Vis reflects the second time derivative of Vic. Vic and Vis were recorded sequentially using standard microelectrode applied to the paced and superfused guinea pig papillary muscles. In the steady state, the greatest negative deflection of Vis (Vmin) was suppressed by quinidine (10 microM) in both PCL- and [K+]e-dependent manner, just like Vmax. However, quinidine-induced greater inhibition of Vmin than Vmax was evident at shorter PCL and greater [K+]e. Based on the sequential alteration of PCL and exposure to ouabain (10 microM), different quinidine sensitivity between Vmax and Vmin is most likely accounted for by the activity-dependent K+ efflux and Na(+)-K+ pump-mediated K+ uptake (i.e., [K+]e fluctuation). Thus, the modulated receptor hypothesis is concluded to be valid in terms of Vis.
Insights
The modulated receptor hypothesis applies to interstitial potential (Vis), not just intracellular potential (Vic). Quinidine
Area of Science:
- Cardiac electrophysiology
- Pharmacology
- Ion channel function
Background:
- The modulated receptor hypothesis explains how antiarrhythmic drugs interact with cardiac ion channels.
- Class I antiarrhythmic agents reduce the maximum upstroke rate (Vmax) of intracellular potential (Vic) in a manner dependent on pacing cycle length (PCL) and external potassium concentration ([K+]e).
Purpose of the Study:
- To investigate the modulated receptor hypothesis concerning interstitial potential (Vis), which reflects the second time derivative of Vic.
- To compare the effects of quinidine on Vmax and Vmin (greatest negative deflection of Vis) under varying PCL and [K+]e.
Main Methods:
- Sequential recording of Vic and Vis using microelectrodes in paced and superfused guinea pig papillary muscles.
- Application of quinidine (10 microM) and ouabain (10 microM) to assess drug effects.
- Alteration of PCL and [K+]e to study dependency.
Main Results:
- Quinidine suppressed Vmin in a PCL- and [K+]e-dependent manner, similar to Vmax.
- Quinidine exhibited greater inhibition of Vmin than Vmax at shorter PCL and higher [K+]e.
- Differential quinidine sensitivity between Vmax and Vmin was linked to activity-dependent K+ efflux and Na(+)-K+ pump activity, causing [K+]e fluctuations.
Conclusions:
- The modulated receptor hypothesis is validated for interstitial potential (Vis).
- Interstitial potential changes, alongside intracellular potential, are crucial for understanding antiarrhythmic drug action.
- Activity-dependent ion flux and pump activity explain observed differences in drug sensitivity between Vmax and Vmin.