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 I-f. A hyperpolarization-activated current I-h, which is present in many types of neurons, is similar to I-f. We studied the effects of these drugs on I-h in cultured mouse dorsal root ganglion (DRG) neurons. 2 With the whole-cell patch-clamp technique use-dependent block of I-h 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 K-d of 0.1 and 0.79 mu M 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 I-h was blocked with UL-FS 49, but not in the absence of Cs+ and UL-FS 49. 7 These results indicate that I-h 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.