Pharmacological characterization of the inwardly-rectifying current in the smooth muscle cells of the rat bladder.

Abstract

1. In freshly-isolated single cells of the rat bladder detrusor, outwardly-rectifying and inwardly-rectifying membrane currents were identified by the whole-cell voltage-clamp technique. 2. The inwardly-rectifying current (IIR) exhibited features of a cation current permeable to both K+ and Na+ but it was unaffected by changes in extracellular Ca2+. It had an activation threshold close to -60 mV and an estimated reversal potential of -29 mV. 3. IIR activated slowly with a voltage-sensitive time-constant of 69 ms at -140 mV and 209 ms at -100 mV but did not exhibit time-dependent inactivation. 4. IIR was unaffected by tetraethylammonium (up to 20 mM) but it was reduced by extracellular Ba2+ (1 mM) and by extracellular Cs+ (1 mM). 5. IIR was reduced by terikalant (100 microM) and markedly inhibited by ciclazindol (100 microM) although at these concentrations, both agents also reduced outward currents. 6. IIR was inhibited by ZD7288 (10-100 microM) in a concentration-dependent manner. At concentrations up to 30 microM, ZD7288 did not reduce the magnitude of outward currents but these were inhibited by 100 microM ZD7288. 7. In strips of bladder detrusor, spontaneous mechanical activity was increased by ZD7288 (0.3-100 microM) and by ciclazindol (0.3-100 microM) but was unaffected by glibenclamide (1-10 microM). 8. It is concluded that IIR closely resembles the hyperpolarization-activated current Ih, 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 confirmed using the inhibitors ZD7288 and ciclazindol.