Use-dependent block of Ih in mouse dorsal root ganglion neurons by sinus node inhibitors.
1. The sinus node inhibitors UL FS 49 and DK-AH 269 reduce heart rate by slowing diastolic depolarization rate in the sino-atrial (SA) node, which might originate from the use-dependent blockade of a hyperpolarization-activated current If. A hyperpolarization-activated current Ih, which is present in many types of neurons, is similar to If. We studied the effects of these drugs on Ih in cultured mouse dorsal root ganglion (DRG) neurons. 2. With the whole-cell patch-clamp technique use-dependent block of Ih was observed. The steady-state block following a voltage-clamp pulse train (1-s steps from -38 to -108 mV applied at 0.5 Hz) was dependent on drug concentration and showed an apparent Kd of 0.1 and 0.79 microM with DK AH 269 and UL-FS 49 respectively. 3. The rate of block increased linearly with drug concentration. The rate of recovery from block was, however, much slower compared to cardiac tissue. 4. There was no significant effect of UL-FS 49 on the activation curve. 5. At high concentrations of UL-FS 49 a clear association of the drug with the open channel was observed. 6. When the cell was stimulated at a frequency of 3 Hz, a distinct hyperpolarization was observed in the presence of extracellular Cs+ or when Ih was blocked with UL-FS 49, but not in the absence of Cs+ and UL-FS 49. 7. These results indicate that Ih protects the cell against hyperpolarizations and subsequent inexcitability. The action of the drugs on the hyperpolarization-activated current in cardiac and neuronal tissue show some similarities; however, some pronounced differences indicate that different subtypes of the channel might exist.
Raes
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A
Department of Biochemistry, Physiology and Genetics, University of Antwerp (RUCA), Belgium.
Van de Vijver
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G
Goethals
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M
van Bogaert
P P
PP
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002586:Cesium / Q000494:pharmacology; D054815:Cyclic Nucleotide-Gated Cation Channels; D005727:Ganglia, Spinal / Q000187:drug effects*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009407:Nerve Block / Q000379:methods*; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000737:chemistry; D015221:Potassium Channels; D012849:Sinoatrial Node / Q000187:drug effects*
D001552:Benzazepines; D002316:Cardiotonic Agents; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; C087873:DK-AH 268; D002586:Cesium; C043636:zatebradine