Abstract
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.
Footnotes
- Received July 31, 2000.
- Accepted October 30, 2000.
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Send reprint requests to: Teresa González, B.S., Institute of Pharmacology and Toxicology, CSIC, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. E-mail:carmenva{at}eucmax.sim.ucm.es
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This study was supported by Comision Interministerial de Ciencia y Tecnologia SAF98-0058 (to C.V.), Comision Interministerial de Ciencia y Tecnologia SAF99-0069 (to J.T.), CAM 08.4/0016198 (to E.D.), and U.S.-Spain Science and Technology Program 98131 (to C.V.) Grants.
- The American Society for Pharmacology and Experimental Therapeutics
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