DELAYED RECTIFIER CURRENT ASSAYS

SINGLE VENTRICULAR MYOCYTES

EFFECTS OF DOFETILIDE ON THE DELAYED RECTIFIER CURRENT I_Kr

Figure 1  Effects of dofetilide on the delayed rectifier current I_Kr.

Figure 1 shows an example of typical I_Kr tail currents recorded by scientists at OCP, under our standard whole-cell patch-clamp conditions for the measurement of native I_K in single left ventricular myocytes.

Figure 1 shows superimposed current records elicited by a 40 ms step depolarisation to +40 mV in the absence (black) and presence (red) of dofetilide (1 µM).

Figure 2   Time course for the effect of dofetilide on the amplitude of I_Kr .

Figure 2  shows that under these conditions tail current amplitude (denoted by black symbols) is stable over the 5 minute control recording period. Application of dofetilide (1 µM) caused a time dependent decrease in the outward tail current consistent with complete block of I_Kr.

Figure 3   Determination of the IC₅₀ of dofetilide on I_Kr measured in single ventricular myocytes.

Figure 3   shows the percentage decrease in the peak amplitude of I_Kr plotted as a function of concentration of dofetilide.

The left hand panel shows the data points taken from individual experiments.

The right hand panel shoes mean±sem data for these experiment.  These data points can be fit by a sigmoid curve (logistic function) which produces and IC₅₀ value of 13±nM.

This value for the potency of dofetilide to block I_Kr in native ventricular myocytes is similar to values reported in the literature for the effect of E-4031 on hERG channels.