Effects of bupivacaine and a novel local anesthetic, IQB-9302, on human cardiac K+ channels

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, K v2.1, Kv4.3, and HERG. Both drugs have a close chemical structure, only dif fering in their N-substituent (n-butyl and cyclopropylmethyl, for bupivacai ne and IQB-9302, respectively). Both drugs blocked Kv2.1, Kv4.3, and HERG c hannels 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 (EC50 = 8.9 +/- 1.4 versus 21.5 +/- 4.7 mM). Both drugs induced a time- and voltage-depende nt block of hKv1.5 and Kv2.1 channels. Block of Kv4.3 channels induced by e ither drug was time- and voltage-dependent at membrane potentials coincidin g with the activation of the channels. IQB-9302 produced an instantaneous b lock of Kv4.3 and hKv1.5 channels at the beginning of the depolarizing puls e that can be interpreted as a drug interaction with a nonconducting state. Bupivacaine and IQB-9302 induced a similar degree of block of HERG channel s and induced a steep voltage-dependent decrease of the relative current. T hese 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.