ACTIVATION BY LEVCROMAKALIM AND METABOLIC INHIBITION OF GLIBENCLAMIDE-SENSITIVE K-CHANNELS IN SMOOTH-MUSCLE CELLS OF PIG PROXIMAL URETHRA

1 The effects of levcromakalim (BRL 38227) on ionic currents recorded from pig proximal urethra were investigated by use of tension measurem ent and patch clamp techniques (conventional whole-cell configuration, nystatin perforated patch, and cell-attached configuration). 2 Levcro makalim (1 mu M) caused a relaxation in the resting tone. This levcrom akalim-induced relaxation was inhibited by the pretreatment with 1 mu M glibenclamide. 3 The resting membrane potential recorded from single cells in current-clamp mode was -36.1 +/- 4.4 mV (n = 5). 4 Levcromak alim induced a concentration-dependent hyperpolarization with a maximu m (at greater than or equal to 10 mu M) close to the theoretical equil ibrium potential of potassium (E(K)). The membrane hyperpolarization c aused by 1 mu M levcromakalim (24.7 +/- 5.8 mV, n = 4) was abolished b y 1 mu M glibenclamide. 5 Levcromakalim (100 mu M) caused an outward K current in whole-cell recordings which was unaffected by iberiotoxin (300 nM) but abolished by glibenclamide (10 mu M). 6 In cell-attached patches, levcromakalim activated a 43 pS K channel which was inhibited by the application of glibenclamide. 7 The metabolic poison, cyanide (CN), also activated a 43 pS K channel which was suppressed by the app lication of 10 mu M glibenclamide. 8 These results indicate that levcr omakalim and metabolic inhibition activate the same 43 pS K channel in pig proximal urethra. The resultant urethral hyperpolarization might reduce the usefulness of K channel openers in the treatment of detruso r instability, but be of value in treating outflow obstruction.