SD-3212, A NEW CLASS-I AND CLASS-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 (I-Ca), the sodium current (I-Na) and the muscarinic acetylcholine-receptor-operated potassium current (I-K.ACh) were examined and compared with those of bepridil in guinea-pig single atrial cells. 2 SD-3212 inhibited I-Ca and I-Na in a concentration-dependent manner. The IC50 values of SD-3212 for inhibition of I-Ca and I-Na were 1.29 mu M and 3.92 mu M, respectively. The steady state inactivation curves of I-Ca and I-Na were shifted in the hyperpolarizing direction in the presence of 1 mu M SD-3212. Similar inhibition of I-Ca and I-Na was also observed with bepridil. The IC50 values of bepridil for depression of I-Ca and I-Na were 1.55 mu M and 4.33 mu M, respectively. 3 The muscarinic acetylcholine-receptor-operated potassium current (I-K.ACh) was activated by the extracellular application of 1 mu M carbachol in the GTP-loaded cells or by the intracellular loading of GTP gamma S, a nonhydrolysable GTP analogue. SD-3212 potently inhibited the carbachol- and GTP mu S-induced I-K.ACh and the IC50 values were 0.38 mu M and 0.20 mu M, respectively. These IC50 values were very close and about 10 times lower than those for inhibiting I-Ca and I-Na. Bepridil also suppressed the carbachol- and GTP gamma S-induced I-K.ACh with the IC50 values of 0.69 mu M and 0.84 mu M, respectively. 4 In guinea-pig atrial cells stimulated at 0.2 Hz, carbachol at a concentration of 1 mu M markedly shortened action potential duration. Both SD-3212 (0.1-1 mu M) and bepridil (1-10 mu M) 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 I-K.ACh 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 I-K.ACh 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.