Multiple actions of U-37883A, an ATP-sensitive K+ channel blocker, on membrane currents in pig urethra

The effects of U-37883A, a vascular ATP-sensitive K+ channel (KATP channel) blocker, on membrane currents were investigated in pig urethral myocytes by use of patch-clamp techniques (conventional whole-cell recordings, nystatin-perforated patches and cell-attached configuration). Tension measurement was also performed to study the effects of U-37883A on the levcromakalim-induced urethral relaxation and the urethral resting tone in the absence and presence of Bay K 8644. Although cumulative application of U-37883A produced a concentration-dependent inhibitory effect on the levcromakalim-induced urethral relaxation, U-37883A did not abolish the relaxation. In nystatin-perforated patch recording, KATP currents activated by levcromakalim were inhibited by U-37883A in a concentration-dependent manner (Ki, 4.7 μM). Approximately 10% of the KATP currents still remained even in the presence of 300 μM U-37883A. In cell-attached mode, extracellular application of U-37883A (100 μM) irreversibly inhibited the activity of the levcromakalim-induced KATP channels. In whole-cell configuration, U-37883A suppressed the peak amplitude of voltage-dependent Ba2+ currents in a concentration- and voltage-dependent manner, and at 30 μM, shifted the steady-state inactivation curve of the Ba2+ currents to the left at − 90 mV. These results demonstrate that U-37883A reduces not only the activities of KATP channels but also voltage-dependent Ca2+ channels. Therefore, it is not appropriate to define U-37883A as solely a vascular KATP channel blocker.