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Vol. 296, Issue 2, 573-583, February 2001

Effects of Bupivacaine and a Novel Local Anesthetic, IQB-9302, on Human Cardiac K+ Channels

Teresa González, Mónica Longobardo, Ricardo Caballero, Eva Delpón, Juan Tamargo and Carmen Valenzuela

Institute of Pharmacology and Toxicology, Consejo Superior de Investigaciones Científicas, School of Medicine, Universidad Complutense, Madrid, Spain

We have studied and compared the effects of bupivacaine with those induced by a new local anesthetic, IQB-9302, on human cardiac K+ channels hKv1.5, Kv2.1, Kv4.3, and HERG. Both drugs have a close chemical structure, only differing in their N-substituent (n-butyl and cyclopropylmethyl, for bupivacaine and IQB-9302, respectively). Both drugs blocked Kv2.1, Kv4.3, and HERG channels similarly. Bupivacaine inhibited these channels by 48.6 ± 3.4, 45.4 ± 12.4, and 43.1 ± 9.1%, respectively, and IQB-9302 by 48.1 ± 3.3, 36.1 ± 3.7, and 50.3 ± 6.6%, respectively. However, bupivacaine was 2.5 times more potent than IQB-9302 to block hKv1.5 channels (EC50 = 8.9 ± 1.4 versus 21.5 ± 4.7 µM). Both drugs induced a time- and voltage-dependent block of hKv1.5 and Kv2.1 channels. Block of Kv4.3 channels induced by either drug was time- and voltage-dependent at membrane potentials coinciding with the activation of the channels. IQB-9302 produced an instantaneous block of Kv4.3 and hKv1.5 channels at the beginning of the depolarizing pulse that can be interpreted as a drug interaction with a nonconducting state. Bupivacaine and IQB-9302 induced a similar degree of block of HERG channels and induced a steep voltage-dependent decrease of the relative current. These results suggest that 1) bupivacaine and IQB-9302 block the open state of hKv1.5, Kv2.1, Kv4.3, and HERG channels; and 2) small differences at the N-substituent of these drugs do not affect the drug-induced block of Kv2.1, Kv4.3, or HERG, but specifically modify block of hKv1.5 channels.

0022-3565/01/2962-0573$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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