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

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. 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 ∼2.5 fold. 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. 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 (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 pH o 6.5 and 7.4, respectively, and that was not observed at pH o 10.0. 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.British Journal of Pharmacology (2001) 134 , 359–369; doi: 10.1038/sj.bjp.0704251