Use-dependent block of I(h) in mouse dorsal root ganglion neurons by sinus node inhibitors

Abstract

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 μM 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.