M. Barann et al., INHIBITION OF 5-HT3 RECEPTOR CATION CHANNELS BY IFENPRODIL IN EXCISEDPATCHES OF N1E-115 CELLS, Naunyn-Schmiedeberg's archives of pharmacology, 358(2), 1998, pp. 145-152
The patch-clamp technique was applied in outside-out patches of NlE-11
5 mouse neuroblastoma cells to investigate the effects of ifenprodil [
(+/-) erythreo-ifenprodil tartrate], a drug with neuroprotective prope
rties in cerebral ischemia, on the inward currents through 5-HT3 recep
tor channels. A high time resolution was achieved by using a rapid sol
ution exchange system (exchange rate <1 ms), Ifenprodil inhibited the
peak currents evoked by 30 mu M 5-HT in a concentration-dependent but
voltage-independent manner, The effect was most potent when ifenprodil
was continuously applied to the patches 45 s before and during the 2-
s administration of 5-HT (IC50=16 mu M) and it was only slightly less
potent when it was applied during the 45 s prior to 5-HT only (IC50=29
mu M). When applied in this manner, ifenprodil also produced a concen
tration-dependent increase of the onset time constant (tau(ON)) of the
5-HT (30 mu M)-induced currents. When the drug was exclusively co-app
lied with 5-HT, ifenprodil was least potent in inhibiting the peak cur
rents (IC50=98 mu M), and it had no effect on the current onset kineti
cs. All protocols of ifenprodil application accelerated current inacti
vation as reflected by a decrease of the current inactivation time con
stant (tau(OFF)) All effects of ifenprodil were reversible after washo
ut periods of 2-5 min. In conclusion, the potency of ifenprodil in inh
ibiting the inward current through 5-HT3 receptor channels is strongly
dependent on the application protocol: presence of the drug before th
e agonist-induced activation of the 5-HT3 receptor channels is necessa
ry for a relatively potent inhibition of the 5-HT-induced peak current
and is a prerequisite for the prolongation of tau(ON) in addition, a
weak but fast inhibitory effect on the current amplitude and decay con
stant of the 5-HT-induced current was revealed by the experiments in w
hich ifenprodil was exclusively present during exposure to 5-HT. Three
alternatives compatible with the components of the ifenprodil effect
have been discussed: (1) different effects of the two enantiomers, (2)
action via two different mechanisms, and (3) operation via a single m
echanism only.