A


REPOLARISATION ASSAYS

SINGLE VENTRICULAR MYOCYTES

EFFECTS OF HALOPERIDOL ON ACTION POTENTIAL DURATION

Figure 1 The effects of haloperidol on action potential duration.

B

Figure1   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 haloperidol (1 and 10 鮦nbsp;

Haloperidol (0.1, 1 and 10 頣aused a concentration-dependent prolongation of APD90. 0.1 ͊ haloperidol prolonged APD90 by 15.4 ⮷ % (see Fig 1A), 1 ࢹ 21.5 䮲%  and 10 ࢹ 53.2 ᰮ9 % (see Fig 1B).  The shape of action potential became close to triangular at the highest concentrations of haloperidol used with a depressed plateau and an unusually extensive prolongation of APD90 (see Fig 1B). 

The effects of haloperidol on APD90 and APD50 are summarised in Figure 2. It is important to note that the actions of haloperidol on APD50 are different from those on APD90: there was a significant increase of 11.3 ⮴% at 0.1 젍 declining to a 33.8 箸% shortening of APD50 at 10 nbsp;The highest concentration of haloperidol caused a 67.9 튠 9.3% reduction in the rate of MRD (p<0.05).


 
 

Figure 2   Mean data for the effect of haloperidol on APD50 and APD90.

 
 

Figure 2 The actions of haloperidol are interesting in that they differ not only from the comparator compounds, dofetilide and sotalol, but also from terfenadine and cisapride.

Prolongation of APD90 observed with haloperidol is consistent with block of IKr, and haloperidol, like terfenadine and cisapride, also reduced MRD (67.9 鮳% decrease at 10 鬠consistent with block of sodium current.  However, unlike the observations with terfenadine and cisapride, the prolonging effect of haloperidol on APD90 appeared not to be counteracted by the possible block of calcium and/or sodium currents.  Indeed the prolongation of APD90 (but not APD50) was even greater than the maximal prolongation seen with dofetilide and sotalol (53.2 ᰮ9% prolongation at 10 mM, compared with the approximately 25% prolongation expected from block of IKr).
It seems possible that the actions of haloperidol may be even more complex than those of terfenadine and cisapride: if haloperidol were to block other outward currents (such as slowly activating IKs or IK1) as well as IKr it may show intense prolongation of APD90 even though these effects may be opposed by block of sodium current.  Depolarisation of membrane potential was observed in some cells in the presence of the highest concentration of haloperidol is consistent with inhibition of IK1.  The effect of 10 ਡloperidol on action potential configuration is marked resulting in an almost triangular action potential (evident as a significant shortening of APD50 by 33.8 箸%) despite the marked increase in APD90.  

In addition to the actions of haloperidol suggested above, a reduction in APD50 may be caused by block of the calcium current which may contribute to the depression of the plateau phase of the action potential (effects of verapamil and nifedipine).

 

 
     
     
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