Effects of ondansetron on apamin-sensitive small conductance calcium-activated potassium currents in pacing-induced failing rabbit hearts

Abstract

, T. H. (2019). Ondansetron effects on apaminsensitive small conductance calcium-activated potassium currents in pacing induced failing rabbit hearts. Heart Rhythm.

Inhibition of Small-Conductance, Ca2+-Activated K+ Current by Ondansetron

“…Our findings also exclude the possibility that ondansetron inhibits native currents expressed in wild type HEK 293 cells. These results are in agreement with our previous observations that ondansetron, when applied in the continuing presence of a saturating apamin concentration, had no effect on whole-cell currents of mouse ventricular myocytes (Ko et al, 2018), nor did it prolong ventricular repolarization of isolated perfused rabbit hearts exposed to low [K + ] o or isolated perfused failing rabbit hearts (Chan et al, 2015;Yin et al, 2020).…”

“…Since under physiological conditions functional SK channels are predominantly present in the atria and control repolarization and excitability (Li et al, 2009;Skibsbye et al, 2014), ondansetron may selectively target atrial SK channels without evoking ventricular proarrhythmia. However, SK channels may importantly contribute to ventricular repolarization in the diseased heart (Chan et al, 2015;Hamilton et al, 2020;Yin et al, 2020), raising the possibility that ondansetron under pathological conditions increases the proarrhythmic risk.…”

Ondansetron blocks wild-type and p.F503L variant small-conductance Ca2+-activated K+ channels

“…Alternatively, ondansetron-induced QT prolongation in our patient may have resulted from inhibition of repolarizing currents other than I KAS [e.g., rapid component of the delayed rectifier K ϩ current (I Kr )]. This appears unlikely, however, because ondansetron in the continual presence of a saturating apamin concentration had no significant effect on APD in low K ϩ concentration-perfused rabbit hearts, in which I Kr is known to significantly contribute to ventricular repolarization (31). Finally, it is also possible that mechanisms not involving KCNE1 and/or ANK2 cause QT prolongation in our patient.…”

“…Ondansetron, when applied in the continuing presence of a saturating apamin concentration, did not significantly alter whole cell currents in ventricular myocytes, nor did it prolong ventricular repolarization in Langendorff-perfused mouse hearts pretreated with ATX-II. Also, we have recently demonstrated that the effects of apamin (100 nM) and ondansetron (100 nM) on ventricular repolarization of isolated perfused rabbit hearts exposed to low extracellular K ϩ concentration are mutually occlusive (31). Collectively, we infer from these findings that ondansetron at nanomolar concentrations selectively targets SK channels under the experimental conditions used.…”

“…Under physiological conditions, SK channels generate very little or no outward current in the ventricle. However, ventricular SK channels elaborate sizable currents in the failing heart and during hypokalemia (4,5,13,31) to maintain a normal repolarization reserve. Here, we identified a rare c.1509CϾG (p.F503L) variant in one KCNN2 allele in a 52-yr-old patient who developed reversible QT interval prolongation after treatment with the 5-HT 3 receptor antagonist ondansetron, a commonly prescribed antiemetic.…”