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 b y slowing diastolic depolarization rate in the sino-atrial (SA) node, which might originate from the use-dependent blockade of a hyperpolari zation-activated current I-f. A hyperpolarization-activated current I- h, which is present in many types of neurons, is similar to I-f. We st udied the effects of these drugs on I-h in cultured mouse dorsal root ganglion (DRG) neurons. 2 With the whole-cell patch-clamp technique us e-dependent block of I-h was observed. The steady-state block followin g a voltage-clamp pulse train (1-s steps from -38 to -108 mV applied a t 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 Th e rate of block increased linearly with drug concentration. The rate o f recovery from block was, however, much slower compared to cardiac ti ssue. 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 stimulat ed at a frequency of 3 Hz, a distinct hyperpolarization was observed i n 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 indic ate that I-h protects the cell against hyperpolarizations and subseque nt inexcitability. The action of the drugs on the hyperpolarization-ac tivated current in cardiac and neuronal tissue show some similarities; however, some pronounced differences indicate that different subtypes of the channel might exist.