The KCa2 Channel Inhibitor AP14145, But Not Dofetilide or Ondansetron, Provides Functional Atrial Selectivity in Guinea Pig Hearts

Figures

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  Figure 1. Flowchart of the Langendorff experiments (left) and in vivo closed chest recordings (right). See text for details.

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  Figure 2. The expression of KCNN1, KCNN2, KCNN3, and KCNH2 relative to the reference genes ACTB and SDHA using qPCR. No significant differences between the right atrium and the left ventricle are observed. Reactions were performed using tissue from five female Dunkin Hartley guinea pigs.

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  Figure 3. Effect of ondansetron on hKCa2.2-expressing HEK cells showing that 1 µM of ondansetron did not inhibit IKCa. Voltage–current (A) and time–current (B) plots showing the effect of 1 µM ondansetron and 100 µM bicuculline methiodide. (C) A bar graph comparing the effects of ondansetron and bicuculline methiodide on IKCa.

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  Figure 4. Effect of ondansetron on hKCa2.3 current showing that up to 30 µM of ondansetron did not inhibit IKCa. Representative current trace (A) and current/time plot (B) showing the effect of increasing concentration of ondansetron. For visual clarity, only the effect of 100 nM, 1 µM, and 10 µM ondansetron is shown in the representative current trace. Currents for I/T plot were measured at the inward current at –80 mV (arrow). 100 µM of bicuculline was added as a reference drug at the beginning and end of the experiment. Because of a current run-up it seems like ondansetron has an activating effect; this run-up is compensated for in the I/T plot. (C) The inhibition curve shows that up to 30 µM ondansetron did not inhibit IKCa.

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  Figure 5. Effect of ondansetron (left) and dofetilide (right) on Kv11.1 current showing that ondansetron blocks the IKr from 3 µM and dofetilide blocks from 0.03 µM. Representative current trace (A, B) and current/time plot (C, D) showing the effect of increasing concentration of ondansetron and dofetilide. For visual clarity, only the effects of 3, 30, and 300 µM ondansetron and 25, 50, and 100 nM dofetilide are shown in the representative current trace. Currents for the I/T plot are measured from the peak tail current (shown with an arrow). 500 nM dofetilide was added as a reference drug at the end of the experiment. (E, F) The inhibition curves showing that ondansetron and dofetilide both inhibit IKr.

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  Figure 6. The effect of AP14145 (1, 10 and 30 µM), dofetilide (3, 10 and 30 nM), and ondansetron (0.3, 1 and 3 µM) on AERP (A), QTcB (B), and heart rate (C) was investigated in perfused Langendorff guinea pig hearts. P-values < 0.05 are given with three decimals in blue for AP14145, red for dofetilide, and purple for ondansetron.

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  Figure 7. The effects of AP14145 (13.3 mg/kg) or dofetilide (0.01 mg/kg) on AERP (A), QTcB (B), and heart rate (C) were investigated in closed chest atrially paced guinea pigs. P-values < 0.05 are given with three decimals in blue for AP14145, and red for dofetilide.