Bupivacaine effects on hKv1.5 channels are dependent on extracellular pH

• Published in: British journal of pharmacology Vol. 134; no. 2; pp. 359 - 369
• Main Authors: Longobardo, M, González, T, Caballero, R, Delpón, E, Tamargo, J, Valenzuela, C
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-09-2001; Nature Publishing
• Subjects: acidosis; Anesthetics, Local - pharmacology; Animals; Biological and medical sciences; Bupivacaine; Bupivacaine - chemistry; Bupivacaine - pharmacology; Dose-Response Relationship, Drug; Drug toxicity and drugs side effects treatment; Electric Stimulation; extracellular pH; hKv1.5; Humans; Hydrogen-Ion Concentration; K+ channels; Kv1.5 Potassium Channel; L Cells (Cell Line); Medical sciences; Membrane Potentials - drug effects; Mice; Pharmacology. Drug treatments; Potassium Channel Blockers; Potassium Channels - physiology; Potassium Channels, Voltage-Gated; Stereoisomerism; Time Factors; Toxicity: cardiovascular system; Toxicity; Electrophysiology; Cardiovascular disease; Ionic channel; Extracellular; In vitro; Myocardial disease; Biological activity; Local anesthetic; Bupivacaine; Heart disease; Established cell line; pH; Organic amide; Membrane potential; Recombinant protein; Mechanism of action; Potassium; Anilide
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0704251

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 (pHo), 6.5, 7.4 and 10.0.
Acidification of the pHo from 7.4 to 6.5 decreased 4 fold the potency of R(+)bupivacaine to block hKv1.5 channels. At pHo 10.0, the potency of the drug increased ∼2.5 fold.
Block induced by R(+)bupivacaine at pHo 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.
At pHo 6.5, but not at pHo 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 (ΔV=−8.5±1.4 mV; n=7).
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 pHo 6.5 and 7.4, respectively, and that was not observed at pHo 10.0.
It is concluded that: (a) alkalinization of the pHo increases the potency of block of R(+)bupivacaine, and (b) at pHo 6.5, R(+)bupivacaine induces an ‘agonist effect’ of hKv1.5 current when recorded at negative membrane potentials.
British Journal of Pharmacology (2001) 134, 359–369; doi:10.1038/sj.bjp.0704251