Stereoselective Interactions of (R)-and (S)-Propafenone with the Cardiac Sodium Channel

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Abstract
Summary The specific interactions of both (R)-and (S)-propafenone with the cardiac sodium channel were studied with patch clamp techniques in the whole-cell recording mode at reduced extracellular Na+ on guinea pig ventricular cells. Both (R)-and (S)-propafenone (10 μ M) shifted the membrane potential required for half-maximal steady-state inactivation (E0.5) of the cardiac sodium channel to considerably more negative membrane potentials [E0.5 = −70.8 ± 2.9 mV for controls vs. −85 ± 3.1 mV for (R)-propafenone and −91.9 ± 1.7 mV for (S)-propafenone]. (S)-Propafenone at a concentration of 10 μ M is more effective in shifting the h curve of the cardiac sodium channel. Recovery from inactivation of the cardiac sodium current is prolonged by orders of magnitude by both stereoenantiomeric forms [time constants were estimated to be 38 ± 15 ms at −90 mV vs. 46.5 ± 14.3 s for (R)-propafenone and 74.2 ± 37.9 s for (S)-propafenone]. Development of block occurs mainly through the inactivated channel conformation for both (R)-and (S)-propafenone. Development of block of inactivated cardiac sodium channels occurs with time constants of 15.9 ± 3.9 s for (R)-propafenone and 19.7 ± 7.3 s for (S)-propafenone at 10 μ M. Action potential duration and possible stereoselective interaction with ion transport systems other than sodium channels may influence the block developed by either (R)-or (S)-propafenone at a given concentration and beating frequency indirectly through the membrane potential. By using only (R)-propafenone rather than racemic (R,S)-propafenone it should be possible to elicit the class Ic antiarrhythmic action of propafenone without simultaneous β-adrenoceptor blocking activities.

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