Selective blockade of the hyperpolarization-activated cationic current (Ih) in guinea pig substantia nigra pars compacta neurones by a novel bradycardic agent, Zeneca ZM 227189.
The effects of a novel bradycardic agent Zeneca ZM 227189 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) triazinium iodide) were tested on the inward rectifying properties of guinea-pig substantia nigra pas compacta (SNC) and guinea-pig olfactory cortical cells recorded in vitro. In SNC neurones, ZM 227189 (10-100 microM) produced a dose-dependent block of the slow anomalous rectifier; under voltage clamp, a clear reduction was seen in the amplitude of the slow inward current (Ih) relaxation evoked by negative voltage commands from a holding potential of -60 mV. ZM 227189 (50-100 microM) induced an irreversible block of the Ih current after 10-15 min exposure. A similar block of Ih was observed following application of 5 mM Cs+. ZM 227189 had little effect on other membrane properties. By contrast, in olfactory cortical neurones, ZM 227189 (100 microM) induced an increase in the input resistance (approximately 20%) and cell excitability, accompanied by a small (< 2 mV) hyperpolarization; these effects were also not reversible. Activation of the fast (K(+)-mediated) inward rectifier at negative membrane potentials remained unaffected. Lower concentrations (1-10 microM) of ZM 227189 had no obvious effect on cortical cell properties. Our data indicate that ZM 227189 is a potent and apparently selective blocker of Ih in substantia nigra neurones, but has no effect on the fast-type inward rectifier in olfactory cortical cells.
Harris
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NC
Department of Pharmacology, School of Pharmacy, London, UK.
Libri
V
V
Constanti
A
A
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002586:Cesium / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009833:Olfactory Pathways / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology*
D000814:Aniline Compounds; D002316:Cardiotonic Agents; D007473:Ion Channels; D014230:Triazoles; C091597:Zeneca ZM 227189; D002586:Cesium