Use‐dependent block of I h 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 μ 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.British Journal of Pharmacology (1998) 125 , 741–750; doi: 10.1038/sj.bjp.0702153