Action of the hyperpolarization-activated current (Ih) blocker ZD 7288 in hippocampal CA1 neurons.
The effects of ZD 7288, a "bradycardic" agent, in young rat hippocampal slices in vitro were studied. ZD 7288 (1-1000 microM) reduced the hyperpolarization-activated current (Ih) in CA1 pyramidal neurons by a voltage-independent blocking mechanism. Under current-clamp conditions, the bradycardic agent (10 microM) caused membrane hyperpolarization (by 5.9 +/- 0.5 mV) and a reduction of membrane conductance (by 17.9 +/- 4.1%). These data are consistent with the block of an inward current which is active at rest. The drug-induced hyperpolarization depressed the cell's excitability by increasing the threshold current necessary to induce firing. When the drug-induced hyperpolarization was compensated for by injection of a tonic depolarizing current, ZD 7288 caused a reduction of the inhibitory post-synaptic potential (IPSP) in EPSP-IPSP sequences. Since Cs+, another known blocker of Ih, is able to reverse long-term depression (LTD) of the CA3-CA1 synapse in hippocampal slices, we tested the effect of ZD 7288 on synaptic transmission. We found that ZD 7288 did not significantly modify LTD, suggesting that Cs+-induced inhibition of LTD maintenance is not directly related to block of Ih.
Gasparini
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S
Università di Milano, Dipartimento di Fisiologia e Biochimica Generali, Elettrofisiologia, via Celoria 26, I-20133 Milan, Italy.
DiFrancesco
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D
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002586:Cesium / Q000494:pharmacology; D004553:Electric Conductivity; D006624:Hippocampus / Q000502:physiology*; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects
D002316:Cardiotonic Agents; D011743:Pyrimidines; C082246:ICI D2788; D002586:Cesium