A classification of antiarrhythmic drugs based on the Na^+ channel blocking properties directly assessed by the cardiac Na^+ current recordings

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There have been considerable variation as to the subclassification of the class I antiarrhythmic drugs depending on the methodology to assess the drug actions, different preparations and individual reporters. As a possible reason for the above confusion, most of the reports dealt with the Na^+ channel block as assessed by measuring V_<max> of action potentials, an indirect index of the Na^+ channel availability rather than the current measurement. Therefore we tried to explore the modes of the Na^+ channel block by class I antiarrhythmic drugs directly assessed by the recordings of the cardiac Na^+ current using the patch-clamp technique and to obtain a new classification of the drugs based on the results. We used isolated ventricular myocytes from guinea-pig hearts by collagenase treatment. The Na^+ currents were recorded by the patch-clamp technique of whole-cell configuration, cell-attached and inside-out patch configurations, Disopyramide, I_a agent, produced used-dependent block of the Na^+ current with two exponential functions, fast and slow component. It was further shown by the experiments conducted under different external pH that the slow block process was caused by ionized form of the drug having affinity to bind the activated state of the Na^+ channel, while the fast process was produced by the non-ionized form to the activated state of the channel. The fast and slow block fractions consisted nearly equal degrees. Lidocaine, I_b agent, also caused two exponential block developments, while the major portion of the block development was brought by the fast fraction with small part by the slow component. The fast block was made by the non-ionized drug to bind the inactivated state of the channel and the slow block was caused by the ionized drug to the activated state of the channel. Mexyletine also caused two exponential block development as similar to lidocaine. The ionized mexiletine pr