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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
Author(s) -
Hara Yukio,
Nakaya Haruaki
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb17237.x
Subject(s) - carbachol , bepridil , muscarinic acetylcholine receptor , chemistry , pharmacology , acetylcholine , endocrinology , calcium , receptor , biochemistry , biology , verapamil , organic chemistry
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 μ m and 3.92 μ m , respectively. The steady state inactivation curves of I ca and I Na were shifted in the hyperpolarizing direction in the presence of 1μ m 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 μ m and 4.43 μ m , 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 KAch and the IC 50 values were 0.38 μ m 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 μ m markedly shortened action potential duration. Both SD‐3212 (0.1−1 μ m ) 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 KAch 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 KAch 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.