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 (K(ATP) 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, K(ATP) currents activated by levcromakalim were inhibited by U-37883A in a concentration-dependent manner (K(i), 4.7 microM). Approximately 10% of the K(ATP) currents still remained even in the presence of 300 microM U-37883A. In cell-attached mode, extracellular application of U-37883A (100 microM) irreversibly inhibited the activity of the levcromakalim-induced K(ATP) channels. In whole-cell configuration, U-37883A suppressed the peak amplitude of voltage-dependent Ba(2+) currents in a concentration- and voltage-dependent manner, and at 30 microM, shifted the steady-state inactivation curve of the Ba(2+) currents to the left at -90 mV. These results demonstrate that U-37883A reduces not only the activities of K(ATP) channels but also voltage-dependent Ca(2+) channels. Therefore, it is not appropriate to define U-37883A as solely a vascular K(ATP) channel blocker.
Tomoda
Toshihisa
T
Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Yunoki
Takakazu
T
Naito
Seiji
S
Ito
Yushi
Y
Teramoto
Noriyoshi
N
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001464:Barium / Q000494:pharmacology; D002120:Calcium Channel Agonists; D019806:Cromakalim / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology*; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000502:physiology; D013552:Swine; D013997:Time Factors; D014521:Urethra / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D002120:Calcium Channel Agonists; D009025:Morpholines; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D014665:Vasodilator Agents; D019806:Cromakalim; D009599:Nitroprusside; D001464:Barium; C082658:U 37883A; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000255:Adenosine Triphosphate; D000218:Adamantane; D005905:Glyburide