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SD‐3212, a new class I and IV antiarrhythmic drug: a potent inhibitor of the muscarinic acetylcholine‐receptor‐operated potassium current in guinea‐pig atrial cells

1 By use of patch‐clamp techniques, the effects of SD‐3212, a novel antiarrhythmic drug, on the calcium current (Ica), the sodium current (INa) and the muscarinic acetylcholine‐receptor‐operated potassium current (IK.ACh) were examined and compared with those of bepridil in guinea‐pig single atrial cells. 2 SD‐3212 inhibited Ica and INa in a concentration‐dependent manner. The IC50 values of SD‐3212 for inhibition of Ica and INa were 1.29 μm and 3.92 μm, respectively. The steady state inactivation curves of Ica and INa were shifted in the hyperpolarizing direction in the presence of 1μm SD‐3212. Similar inhibition of Ica and INa was also observed with bepridil. The IC50 values of bepridil for depression of Ica and INa were 1.55 μm and 4.43 μm, respectively. 3 The muscarinic acetylcholine‐receptor‐operated potassium current (IK.ACh) was activated by the extracellular application of 1 μm carbachol in the GTP‐loaded cells or by the intracellular loading of GTPγS, a nonhydrolysable GTP analogue. SD‐3212 potently inhibited the carbachol‐ and GTPγS‐induced IKAch and the IC50 values were 0.38 μm and 0.20 μm, respectively. These IC50 values were very close and about 10 times lower than those for inhibiting Ica and INa. Bepridil also suppressed the carbachol‐ and GTPγS‐induced IK.ACh with the IC50 values of 0.69 μm and 0.84 μm, respectively. 4 In guinea‐pig atrial cells stimulated at 0.2 Hz, carbachol at a concentration of 1 μm markedly shortened action potential duration. Both SD‐3212 (0.1−1 μm) and bepridil (1–10 μm) reversed the action potential shortening in a concentration‐dependent manner. The antagonizing effect of SD‐3212 on the carbachol‐induced action potential shortening was more potent than that of bepridil. 5 These results suggest that SD‐3212 inhibits IKAch by depressing the function of the potassium channel itself and/or associated GTP‐binding proteins. SD‐3212 is a unique antiarrhythmic drug, which potently inhibits IKAch in addition to its class I and IV effects. SD‐3212 and bepridil may be useful for the termination and prevention of vagally‐induced atrial flutter and fibrillation.