REPOLARISATION ASSAYS

SINGLE VENTRICULAR MYOCYTES

EFFECTS OF CISAPRIDE ON ACTION POTENTIAL DURATION

Figure 1 The effects of cisapride on action potential duration.

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 cisapride (0.1 and 10 鮦nbsp;

The lowest concentration of cisapride used (0.1 é £aused a significant 16.6 á®´% prolongation of APD₉₀ (p<0.05 at 1 Hz, see Fig 1A).  However, as the concentration of cisapride was increased the prolonging effects on APD₉₀ were diminished such that 1 ࣩsapride only prolonged APD₉₀ by 9.6 튠 2.8%, and 10 ࣩsapride caused a non-significant shortening of APD₉₀ by 0.5 ⮸% (see Fig 1B and Fig 2).  

The effects of 0.1 and 1 ࣩsapride on APD₅₀ were broadly similar to those on APD₉₀.  However, at the highest concentration of cisapride 10 à´¨ere was a significant decrease in APD₅₀ and triangulation of the action potential was evident (see Fig 2B). At the highest concentration (10 鬠cisapride caused a significant 9.0 ⮲ % (p<0.05) reduction in the rate of rise of the action potential (MRD), though the effects were not significant at the lower concentrations.

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

Figure 2 shows that the actions of cisapride on action potential configuration differ from those of the comparator compounds, dofetilide and sotalol.  A significant prolongation of APD₉₀ was detected at 100 nM, but effects on APD₉₀ appeared to decrease as the concentration was increased. The following the arguments to explain the effects of cisapride on APD₉₀ equally apply to the effects of terfenadine.

These data are consistent with a cisapride block of I_Kr at lower concentrations (Drolet et al., 1998), causing prolongation of action potential duration.  However, higher concentrations of cisapride may block other ionic currents, such as sodium or calcium currents, that oppose the effects of blocking I_Kr and may result in a profound alteration in the configuration of the action potential (see action potential triangulation Fig 1B).  As with terfenadine, cisapride reduced MRD (by 9.0 ⮲% at 10 mM), consistent with additional block of the sodium current.  Another point to be noted is that at the highest concentration of cisapride caused a greater reduction in APD₅₀ than APD₉₀, which has been previously observed with calcium channel inhibition (Cerbai et al, 1990, see the effects of nifedipine and verapamil on action potential configuration and the effects of nifedipine on the calcium current).  A similar biphasic action of compounds that inhibit both I_Kr and I_Ca on action potential duration (prolongation at low drug concentrations and shortening at high drug concentrations) has been previously observed (Bril et al, 1998).

References

Cerbai, E., DeBonfioli Cavalcabo, P., Masini, I., Visentin, S., Giotti, A. and Mugelli, A. (1990) Cardiac electrophysiologic effects of a new calcium antagonist, lacidpine. J of CV Pharm. 15:604-609

Bril, A., Forest, M-C., Cheval, B., Faivre, J-F. (1998) Combined potassium and calcium channel antagonistic activities as a basis for neutral frequency-dependent increase in action potential duration: comparison between BRL-32872 and azimilide. CV Res. 37: 130-140