SELECTIVE BLOCKADE OF THE HYPERPOLARIZATION-ACTIVATED CATIONIC CURRENT (I-H) IN GUINEA-PIG SUBSTANTIA-NIGRA PARS COMPACTA NEURONS BY A NOVEL BRADYCARDIAC AGENT, ZENECA ZM-227189
Nc. Harris et al., SELECTIVE BLOCKADE OF THE HYPERPOLARIZATION-ACTIVATED CATIONIC CURRENT (I-H) IN GUINEA-PIG SUBSTANTIA-NIGRA PARS COMPACTA NEURONS BY A NOVEL BRADYCARDIAC AGENT, ZENECA ZM-227189, Neuroscience letters, 176(2), 1994, pp. 221-225
The effects of a novel bradycardic agent Zeneca ZM 227189 -ethyl-N-phe
nylamino)-1,2-dimethyl-6-(methylamino) triazinium iodide) were tested
on the inward rectifying properties of guinea-pig substantia nigra par
s compacta (SNC) and guinea-pig olfactory cortical cells recorded in v
itro. In SNC neurones, ZM 227189 (10-100 mu M) produced a dose-depende
nt block of the slow anomalous rectifier; under voltage clamp, a clear
reduction was seen in the amplitude of the slow inward current (I-h)
relaxation evoked by negative voltage commands from a holding potentia
l of -60 mV. ZM 227189 (50-100 mu M) induced an irreversible block of
the I-h current after 10-15 min exposure. A similar block of I-h was o
bserved following application of 5 mM Cs+. ZM 227189 had little effect
on other membrane properties. By contrast, in olfactory cortical neur
ones, ZM 227189 (100 mu M) induced an increase in the input resistance
(similar to 20%) and cell excitability, accompanied by a small (<2 mV
) hyperpolarization; these effects were also not reversible. Activatio
n of the fast (K+-mediated) inward rectifier at negative membrane pote
ntials remained unaffected. Lower concentrations (1-10 mu M) of ZM 227
189 had no obvious effect on cortical cell properties. Our data indica
te that ZM 227189 is a potent and apparently selective blocker of I-h
in substantia nigra neurones, but has no effect on the fast-type inwar
d rectifier in olfactory cortical cells.