NICORANDIL ACTIVATES GLIBENCLAMIDE-SENSITIVE K-MUSCLE CELLS OF PIG PROXIMAL URETHRA( CHANNELS IN SMOOTH)

The effects of nicorandil on ionic currents recorded from single smoot h muscle cells of pig proximal urethra were investigated using patch-c lamp techniques. Tension measurement was also performed to study the e ffects of nicorandil on the resting tone of pig urethra. Nicorandil pr oduced a concentration-dependent sustained outward current that was su ppressed by glibenclamide at -50 mV and was carried selectively by K+. In cell-attached configuration, nicorandil activated a 43-pS K+ chann el that was reversibly inhibited by 10 mu M glibenclamide. This gliben clamide-sensitive 43-pS K+ channel (K-GS) ''ran down'' after excision of the membrane patch. In inside-out configuration, the application of either 1 mM Mg-ATP or 1 mM nucleotide diphosphate reactivated the K-G S. In symmetrical 140 mM K+ conditions, 300 mu M nicorandil and 300 mu M levcromakalim activated a 2.14-pA K+ channel that exhibited the sam e amplitude and similar channel-opening kinetics. Methylene blue (10-1 00 mu M), a soluble guanylate cyclase inhibitor, did not inhibit the o pening of the nicorandil-induced K-GS. The K-GS was not activated by e ither sodium nitroprusside (10-100 mu M) or 8-bromo guanosine 3':5'-cy clic monophosphate (1 mM). Nicorandil caused a concentration-dependent relaxation of the urethral resting tone but was less potent than levc romakalim. The relaxation induced by 10 mu M nicorandil was partially inhibited by glibenclamide (1-10 mu M) and also by methylene blue (10- 100 mu M). These results indicate that two independent nicorandil-indu ced relaxation mechanisms may be present in pig urethra.