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REPOLARISATION ASSAYS
SINGLE VENTRICULAR MYOCYTES
EFFECTS OF
CISAPRIDE ON ACTION POTENTIAL DURATION
Figure 1
The effects of cisapride on action potential duration.
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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 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 íŠ 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 é¬ 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.
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Figure 2
Mean data for the effect of cisapride on APD50 and APD90.
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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 IKr 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 IKr 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 IKr and ICa
on action potential duration (prolongation at low drug concentrations and
shortening at high drug concentrations) has been previously observed (Bril
et al, 1998).
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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
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