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

  1. Teresa González,
  2. Mónica Longobardo,
  3. Ricardo Caballero,
  4. Eva Delpón,
  5. Juan Tamargo and
  6. Carmen Valenzuela
  1. Institute of Pharmacology and Toxicology, Consejo Superior de Investigaciones Cientı́ficas, School of Medicine, Universidad Complutense, Madrid, Spain

    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

    • 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

    • 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.

    • Abbreviations:
      IKur
      ultrarapid delay rectifier potassium current
      ITO
      transient outward potassium current
      IKr
      rapid delay rectifier potassium current
      IV
      current-voltage relationship
      τB
      time constant of block
      δ
      fractional electrical distance
      Eh
      voltage at which 50% of the channels are open
      • Received July 31, 2000.
      • Accepted October 30, 2000.
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    1. JPET February 1, 2001 vol. 296 no. 2 573-583
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