title: Effects of bupivacaine and a novel local anesthetic, IQB-9302, on human cardiac K+ channels.
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 (EC(50) = 8.9 +/- 1.4 versus 21.5 +/- 4.7 microM). 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.
authors.affiliation: Institute of Pharmacology and Toxicology, Consejo Superior de Investigaciones Científicas, School of Medicine, Universidad Complutense, Madrid, Spain.
authors.forename: T
authors.initials: T
authors.lastname: González
authors.forename: M
authors.initials: M
authors.lastname: Longobardo
authors.forename: R
authors.initials: R
authors.lastname: Caballero
authors.forename: E
authors.initials: E
authors.lastname: Delpón
authors.forename: J
authors.initials: J
authors.lastname: Tamargo
authors.forename: C
authors.initials: C
authors.lastname: Valenzuela
mesh_terms: D000465:Algorithms; D000779:Anesthetics, Local; D000818:Animals; D002045:Bupivacaine / Q000494:pharmacology*; D027682:Cation Transport Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins; D051668:Delayed Rectifier Potassium Channels; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D006321:Heart / Q000187:drug effects; D006801:Humans; D051666:Kv1.5 Potassium Channel; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D051669:Shab Potassium Channels; D051672:Shal Potassium Channels; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
chemical_list: D000779:Anesthetics, Local; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D051668:Delayed Rectifier Potassium Channels; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C418003:IQB 9302; C496981:KCNA5 protein, human; C496988:KCNB1 protein, human; C497021:KCND3 protein, human; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D051666:Kv1.5 Potassium Channel; D010880:Piperidines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051669:Shab Potassium Channels; D051672:Shal Potassium Channels; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D002045:Bupivacaine