Modulation of the hyperpolarisation-activated current, Ih, in rat facial motoneurones in vitro by ZD-7288

ZD-7288 [4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride] and Cs' have been used to distinguish the currents contributing to inward rectification in neonatal rat facial motoneurones (FMs). ZD-7288 (0.1-10 muM) inhibited a current that reversed at -43.7 +/-3.7 mV in artificial cerebrospinal fluid (ACSF) containing 3 mM K+ (n = 9), and displayed the time and voltage dependence of the hyperpolarisation-activated current, I-h. Depolarisation-activated transient (I-K(A)) and sustained outward currents were unaffected by ZD-7288. The IC50 for block of I-h by ZD-7288 was around 0.2 muM. Onset of inhibition was slow and no recovery was seen after washing in ZD-7288-free ACSF for up to 4 h. In the presence of ZD-7288, Ba2+ and Rb+ blocked an inwardly rectifying potassium (KC) current, confirming both the presence of I-K(IR) and its insensitivity to ZD-7288, Csf rapidly and reversibly blocked both I-h and I-K(IR). Inhibition of I-h by ZD-7288 showed no use dependence, internally applied ZD-7288 also blocked I-h. and tail current analysis indicated inhibition to be voltage-independent. In the presence of internal guanosine 5 ' -O-(3-thiotriphosphate) (GTP-gamma -S) and after previous exposure to ZD-7288, 5-hydroxytryptamine (5-MT), but not noradrenaline. promoted a recovery of I, that was not observed if ZD-7288 was present throughout the recording period. This interaction between ZD-7288 and irreversible 5-MT-receptor activation may be related to the mechanism underlying ZD-7288-mediated block of these channels. (C) 2001 Elsevier Science Ltd. All rights reserved.