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*AMITRIPTYLINE

Vol. 292, Issue 3, 1015-1023, March 2000

Block of Human Heart hH1 Sodium Channels by Amitriptyline1

Carla Nau, Margaret Seaver, Sho-Ya Wang and Ging Kuo Wang

Department of Biology, State University of New York, Albany, New York (M.S., S.-Y.W.); and Department of Anesthesia, Harvard Medical School and Brigham & Women's Hospital, Boston, Massachusetts (C.N., G.K.W.)

Amitriptyline is a tricyclic antidepressant used to treat major depression and various neuropathic pain syndromes. This drug also causes cardiac toxicity in patients with overdose. We characterized the tonic and use-dependent amitriptyline block of human cardiac (hH1) Na+ channels expressed in human embryonic kidney cells under voltage-clamp conditions. Our results show that, near the therapeutic plasma concentration of 1 µM, amitriptyline is an effective use-dependent blocker of hH1 Na+ channels during repetitive pulses (~55% block at 5 Hz). The tonic block for resting and for inactivated hH1 channels by amitriptyline (0.1-100 µM) yielded IC50 values (50% inhibitory concentration) of 24.8 ± 2.0 (n = 9) and 0.58 ± 0.03 µM (n = 7), respectively. Substitution of phenylalanine with lysine at the hH1-F1760 position, a putative binding site for local anesthetics, eliminates the use-dependent block by amitriptyline at 1 µM. The time constants of recovery from the inactivated-state amitriptyline block in hH1 wild-type and hH1-F1760K mutant channels are 8.0 ± 0.5 (n = 6) and 0.45 ± 0.07 s (n = 6), respectively. A substitution at either hH1-F1760K or hH1-Y1767K significantly increases the IC50 values for resting and inactivated states of amitriptyline, but the increase is much more pronounced with the hH1-F1760K mutation. Because these two residues were proposed to form a part of the local anesthetic binding site, we conclude that amitriptyline and local anesthetics interact with a common binding site. Furthermore, at therapeutic concentrations, the ability of amitriptyline to act as a potent use-dependent blocker of Na+ channels may, in part, explain its analgesic actions.

1 This work was supported by Grant GM-48090 from the National Institutes of Health.

0022-3565/00/2923-1015$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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