Nicorandil activates glibenclamide-sensitive K+ channels in smooth muscle cells of pig proximal urethra.
The effects of nicorandil on ionic currents recorded from single smooth muscle cells of pig proximal urethra were investigated using patch-clamp techniques. Tension measurement was also performed to study the effects of nicorandil on the resting tone of pig urethra. Nicorandil produced a concentration-dependent sustained outward current that was suppressed by glibenclamide at -50 mV and was carried selectively by K+. In cell-attached configuration, nicorandil activated a 43-pS K+ channel that was reversibly inhibited by 10 microM glibenclamide. This glibenclamide-sensitive 43-pS K+ channel (KGS) "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 KGS. In symmetrical 140 mM K+ conditions, 300 microM nicorandil and 300 microM levcromakalim activated a 2.14-pA K+ channel that exhibited the same amplitude and similar channel-opening kinetics. Methylene blue (10-100 microM), a soluble guanylate cyclase inhibitor, did not inhibit the opening of the nicorandil-induced KGS. The KGS was not activated by either sodium nitroprusside (10-100 microM) or 8-bromo guanosine 3':5'-cyclic monophosphate (1 mM). Nicorandil caused a concentration-dependent relaxation of the urethral resting tone but was less potent than levcromakalim. The relaxation induced by 10 microM nicorandil was partially inhibited by glibenclamide (1-10 microM) and also by methylene blue (10-100 microM). These results indicate that two independent nicorandil-induced relaxation mechanisms may be present in pig urethra.
Teramoto
N
N
University Department of Pharmacology, Oxford, U.K.
Brading
A F
AF
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D019806:Cromakalim; D006152:Cyclic GMP / Q000502:physiology; D005260:Female; D005905:Glyburide / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology; D013552:Swine; D014521:Urethra / Q000187:drug effects* / Q000502:physiology
D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D009536:Niacinamide; D020108:Nicorandil; D000255:Adenosine Triphosphate; D006152:Cyclic GMP; D005905:Glyburide