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

Abstract

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.