Background: Ondansetron (Htr3a antagonist) has been reported to prolong the QT interval and induce Torsades de pointes in the treatment of postoperative nausea and vomiting. To explore the mechanisms underlying these findings, we examined the effects of ondansetron on the mouse cardiac voltage-gated K+ (Kv) channel.
Methods and Results: Ondansetron increased QT intervals in LP mice. We measured the Kv channels in the freshly-isolated left ventricular (LV) myocytes from non-pregnant (NP) and pregnant (LP) mice, using patch-clamp electrophysiology. Ondansetron (50 μM) blocked Kv current, and reduced peak current densities amplitude in a dose-dependent manner (0, 1, 5, 50 μM), in LP but not in NP mice. In contrast, serotonin and Htr3 agonist (m-CPBG) increased Kv current densities in NP, but not in LP mice. Interestingly, during pregnancy, serum serotonin levels were markedly increased suggesting the saturation of the effect of serotonin. Immunostaning data showed that Kv4.3 protein and Htr3a is co-localization in the membrane and t-tubule of cardiomyocytes. Moreover, we found that the enhanced Kv4.3 membrane trafficking in response to Htr3a-mediated serotonin stimulation in NP, but not in LP mice. Membrane analysis shows that the serotonin enhances Kv4.3 membrane trafficking in NP, but not LP mice.
Conclusion: Ondansetron reduced Kv current densities, and reduced the Kv4.3 membrane trafficking in LP mouse ventricular cardiomyocytes. This data suggested that QT prolongation by ondansetron is medicated by the reduction of Kv current densities and Kv4.3 membrane trafficking.
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