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

摘要

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 IC_(50) values of SD-3212 for inhibition of I_(Ca) and I_(Na) were 1.29 μM and 3.92 μM, respectively. The steady state inactivation curves of I_(Ca) and I_(Na) were shifted in the hyperpolarizing direction in the presence of 1 μM SD-3212. Similar inhibition of I_(Ca) and I_(Na) was also observed with bepridil. The IC_(50) values of bepridil for depression of I_(Ca) and I_(Na) were 1.55 μM and 4.43 μM, respectively. 3 The muscarinic acetylcholine-receptor-operated potassium current (I_(K.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 I_(K.ACh) and the IC_(50) values were 0.38 μM and 0.20 μM respectively. These IC_(50) values were very close and about 10 times lower than those for inhibiting I_(Ca) and I_(Na). Bepridil also suppressed the carbachol- and GTPγS-induced I_(K.ACh) with the IC_(50) 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 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.