Interactions of the 5-hydroxytryptamine 3 antagonist class of antiemetic drugs with human cardiac ion channels

Administration of the 5-hydroxytryptamine 3 receptor class of antiemetic ag ents has been associated with prolongation in the QRS, JT, and QT intervals of the ECG. To explore the mechanisms underlying these findings, we examin ed the effects of granisetron, ondansetron, dolasetron, and the active meta bolite of dolasetron MDL 74,156 on the cloned human cardiac Na+ channel hH1 and the human cardiac K+ channel HERG and the slow delayed rectifier K+ ch annel KvLQT1/minK. Using patch-clamp electrophysiology we found that all of the drugs blocked Na+ channels in a frequency-dependent manner. At a frequ ency of 3 Hz, the IC50 values for block of Na+ current measured 2.6, 88.5, 38.0, and 8.5 muM for granisetron, ondansetron, dolasetron, and MDL 74,156, respectively. Block was relieved by strong hyperpolarizing potentials, sug gesting a possible interaction with an inactivated channel state. Recovery from inactivation was impaired at -80 mV compared with -100 mV, and the fra ctional recovery was impaired by drug in a concentration-dependent manner. IC50 values for block of the HERG cardiac K+ channel measured 3.73, 0.81, 5 .95, and 12.1 mM for granisetron, ondansetron, dolasetron, and MDL 74,156, respectively. Ondansetron (3 muM) also slowed decay of HERG tail currents. In contrast, none of these drugs (10 muM) produced greater than 30% block o f the slow delayed rectifier K+ channel KvLQT1/minK. We concluded that the antiemetic agents tested in this study block human cardiac Na+ channels pro bably by interacting with the inactivated state. This may lead to clinicall y relevant Na+ channel blockade, especially when high heart rates or depola rized/ischemic tissue is present. The submicromolar affinity of ondansetron for the HERG K+ channel likely underlies the prolongation of cardiac repol arization reported for this drug.