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

I 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 similar to2.5 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 hKvl.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.