PHARMACOLOGICAL CHARACTERIZATION OF THE INWARDLY-RECTIFYING CURRENT IN THE SMOOTH-MUSCLE CELLS OF THE RAT BLADDER

1 In freshly-isolated single cells of the rat bladder detrusor, outwar dly-rectifying and inwardly-rectifying membrane currents were identifi ed by the whole-cell voltage-clamp technique. 2 The inwardly-rectifyin g current (I-IR) exhibited features of a cation current permeable to b oth K+ and Na+ but it was unaffected by changes in extracellular Ca2+. It had an activation threshold close to -60 mV and an estimated rever sal potential of -29 mV. 3 I-IR activated slowly with a voltage-sensit ive time-constant of 69 ms at -140 mV and 209 ms at -100 mV but it did not exhibit time-dependent inactivation.4 I-IR was unaffected by tetr aethylammonium (up to 20 mM) but it was reduced by extracellular Ba2(1 mM) and by extracellular Cs+ (1 mM). 5 I-IR was reduced by terikala nt (100 mu M) and markedly inhibited by ciclazindol (100 mu M) althoug h at these concentrations, both agents also reduced outward currents. 6 I-IR was inhibited by ZD7288 (10-100 mu M) in a concentration-depend ent manner. At concentrations up to 30 mu M, ZD7288 did not reduce the magnitude of outward currents but these were inhibited by 100 mu M ZD 7288. 7 In strips of bladder detrusor, spontaneous mechanical activity was increased by ZD7288 (0.3-100 mu M) and by ciclazindol (0.3 - 100 mu M) but was unaffected by glibenclamide (1-10 mu M). 8 It is conclud ed that I-IR closely resembles the hyperpolarization-activated current , I-h, previously described in the smooth muscle of rabbit jejunum and in a variety of other cell types. This current may play an important role in modulating detrusor excitability but this could not be confirm ed using the inhibitors ZD7288 and ciclazindol.