REPOLARISATION ASSAYS

SINGLE VENTRICULAR MYOCYTE

EFFECTS OF DOFETILIDE ON ACTION POTENTIAL DURATION

Figure 1 The effect of dofetilide on action potential duration.

Figure 1 shows action potential records taken from a single left ventricular myocyte under our standard experimental conditions used for the action potential measurements in the absence (black) and presence (red) of dofetilide (1 鮠

Application of dofetilide (1, 10, 100 and 1000 nM) caused a concentration-dependent increase in action potential duration. The effects are summarised in Figure 2.  10 nM dofetilide prolonged APD90 by 7.7 ᮷% and 100 nM dofetilide prolonged APD90 by 23.4 ᮴% (p<0.01 in both cases).  APD50 was prolonged by a similar extent by dofetilide.  

No significant effect of dofetilide on the maximal rate of depolarisations (MRD) was detected with these concentrations.  The effect of 1 यfetilide on APD90 and APD50 was similar to that observed with 100 nM dofetilide.


 

Figure 2  Mean data for the effect of dofetilide on APD.

 
 

Dofetilide is used here as a potent comparator compound. As expected, dofetilide caused a concentration-dependent prolongation of action potential duration which was evident as significant increases in both APD50 and APD90.  The maximum prolongation of APD90 amounted to 23.4 ᮴% at 100 nM. Notably, increasing the concentration of dofetilide to 1 젤id not further increase the prolongation of APD90 (see Fig 2). This is consistent with complete inhibition of IKr which is seen to occur at concentrations of 100 nM.  No change in MRD was detected at the concentrations used.  

Since dofetilide is recognised to be a very specific inhibitor of IKr, with little or no actions on other cardiac ionic currents at the concentrations tested, the observed actions are therefore those that are expected for this comparator compound.  The maximum prolongation of action potential which occurred with complete inhibition of IKr by dofetilide, should be borne in mind when considering actions of other compounds.

The significant prolongation of cardiac repolarisation would be expected to result in QT prolongation in the intact heart and increase the risk of arrhythmia. Dofetilide-induced prolongation of the action potential is due to dofetilide-induced block of IKr

   
   
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