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Vol. 295, Issue 2, 614-620, November 2000
Aventis Pharmaceuticals, Inc., Bridgewater, New Jersey (L.W.,
C.R.B., D.R.); ChanTest, Inc., Cleveland, Ohio (Y.A.K., A.M.B.); and
Rammelkamp Center for Education and Research, MetroHealth Campus, Case
Western Reserve University, Cleveland, Ohio (Y.A.K., A.M.B.)
Administration of the 5-hydroxytryptamine 3 receptor class of
antiemetic agents has been associated with prolongation in the QRS, JT,
and QT intervals of the ECG. To explore the mechanisms underlying these
findings, we examined the effects of granisetron, ondansetron,
dolasetron, and the active metabolite 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+ channel KvLQT1/minK. Using patch-clamp electrophysiology
we found that all of the drugs blocked Na+ channels in a
frequency-dependent manner. At a frequency of 3 Hz, the
IC50 values for block of Na+ current measured
2.6, 88.5, 38.0, and 8.5 µM for granisetron, ondansetron, dolasetron,
and MDL 74,156, respectively. Block was relieved by strong
hyperpolarizing potentials, suggesting a possible interaction with an
inactivated channel state. Recovery from inactivation was impaired at
80 mV compared with 100 mV, and the fractional 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 µM for granisetron, ondansetron,
dolasetron, and MDL 74,156, respectively. Ondansetron (3 µM) also
slowed decay of HERG tail currents. In contrast, none of these drugs
(10 µM) produced greater than 30% block of the slow delayed
rectifier K+ channel KvLQT1/minK. We concluded that the
antiemetic agents tested in this study block human cardiac
Na+ channels probably by interacting with the inactivated
state. This may lead to clinically relevant Na+ channel
blockade, especially when high heart rates or depolarized/ischemic tissue is present. The submicromolar affinity of ondansetron for the
HERG K+ channel likely underlies the prolongation of
cardiac repolarization reported for this drug.
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