Bupivacaine effects on hKv1.5 channels are dependent on extracellular pH.
1. Bupivacaine-induced cardiotoxicity increases in hypoxic and acidotic conditions. We have analysed the effects of R(+)bupivacaine on hKv1.5 channels stably expressed in Ltk(-) cells using the whole-cell patch-clamp technique, at three different extracellular pH (pH(o)), 6.5, 7.4 and 10.0. 2. Acidification of the pH(o) from 7.4 to 6.5 decreased 4 fold the potency of R(+)bupivacaine to block hKv1.5 channels. At pH(o) 10.0, the potency of the drug increased approximately 2.5 fold. 3. Block induced by R(+)bupivacaine at pH(o) 6.5, 7.4 and 10.0, was voltage- and time-dependent in a manner consistent with an open state block of hKv1.5 channels. 4. At pH(o) 6.5, but not at pH(o) 7.4 or 10.0, R(+)bupivacaine increased by 95+/-3 % (n=6; P<0.05) the hKv1.5 current recorded at -10 mV, likely due to a drug-induced shift of the midpoint of activation (DeltaV=-8.5+/-1.4 mV; n=7). 5. R(+)bupivacaine development of block exhibited an 'instantaneous' component of block at the beginning of the depolarizing pulse, which averaged 12.5+/-1.8% (n=5) and 4.6+/-1.6% (n=6), at pH(o) 6.5 and 7.4, respectively, and that was not observed at pH(o) 10.0. 6. It is concluded that: (a) alkalinization of the pH(o) increases the potency of block of R(+)bupivacaine, and (b) at pH(o) 6.5, R(+)bupivacaine induces an 'agonist effect' of hKv1.5 current when recorded at negative membrane potentials.
Longobardo
M
M
Institute of Pharmacology and Toxicology CSIC/UCM, School of Medicine, Universidad Complutense, 28040 Madrid, Spain.
González
T
T
Caballero
R
R
Delpón
E
E
Tamargo
J
J
Valenzuela
C
C
D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002045:Bupivacaine / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051666:Kv1.5 Potassium Channel; D007739:L Cells; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D013237:Stereoisomerism; D013997:Time Factors
D000779:Anesthetics, Local; C496981:KCNA5 protein, human; C496982:Kcna5 protein, mouse; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D002045:Bupivacaine