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Vol. 293, Issue 1, 196-205, April 2000

Tertiapin Potently and Selectively Blocks Muscarinic K+ Channels in Rabbit Cardiac Myocytes1

Hidetsuna Kitamura , Mitsuhiro Yokoyama, Hozuka Akita, Kenji Matsushita, Yoshihisa Kurachi and Mitsuhiko Yamada

Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Suita, Osaka, Japan (H.K., M.Ya.); First Department of Internal Medicine, Kobe University School of Medicine, Kobe, Japan (H.K., M.Yo., H.A.); and Department of Pharmacology II, Faculty of Medicine, Osaka University, Osaka, Japan (K.M., Y.K.)

Tertiapin is a 21-residue peptide isolated from honey bee venoms. A recent study indicated that tertiapin is a potent blocker of certain types of inwardly rectifying K+ (Kir) channels (Jin and Lu, 1998). We examined the effect of tertiapin on ion channel currents in rabbit cardiac myocytes using the patch-clamp technique. In the whole-cell configuration, tertiapin fully inhibited acetylcholine (1 µM)-induced muscarinic K+ (KACh) channel currents in atrial myocytes with the half-maximum inhibitory concentration of ~8 nM through ~1:1 stoichiometry. The potency of tertiapin in inhibiting KACh channels was not significantly different at -40 and -100 mV. Tertiapin also inhibited the KACh channel preactivated by intracellular guanosine 5'-O-(3-thiotriphosphate), a nonhydrolyzable GTP analog. A constitutively active Kir channel, the IK1 channel, was at least 100 times less sensitive to tertiapin. Another Kir channel in cardiac myocytes, the ATP-sensitive K+ channel, was virtually insensitive to tertiapin (1 µM). The voltage-dependent K+ and the L-type Ca2+ channels were not affected by tertiapin (1 µM). At the single-channel level, tertiapin inhibited the KACh channel from the outside of the membrane by reducing the NPo (N is the number of functional channels, and the Po is the open probability of each channel) without affecting the single-channel conductance or fast kinetics. Therefore, tertiapin potently and selectively blocks the KACh channel in cardiac myocytes in a receptor- and voltage-independent manner. Tertiapin is a novel pharmacological tool to identify the functional role of the KACh channel in the parasympathetic regulation of the heart beat.

1 This work was supported by a Research Grant for Cardiovascular Diseases (11C-1) from the Ministry of Health and Welfare of Japan and a grant from Japan Cardiovascular Research Foundation to M. Yamada.

0022-3565/00/2931-0196$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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