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 measurement and patch clamp techniques (conventional whole-cell configuration, nystatin perforated patch, and cell-attached configuration). 2. Levcromakalim (1 microM) caused a relaxation in the resting tone. This levcromakalim-induced relaxation was inhibited by the pretreatment with 1 microM glibenclamide. 3. The resting membrane potential recorded from single cells in current-clamp mode was-36.1 +/- 4.4 mV (n = 5). 4. Levcromakalim induced a concentration-dependent hyperpolarization with a maximum (at > or = 10 microM) close to the theoretical equilibrium potential of potassium (EK). The membrane hyperpolarization caused by 1 microM levcromakalim (24.7 +/- 5.8 mV, n = 4) was abolished by 1 microM glibenclamide. 5. Levcromakalim (100 microM) caused an outward K current in whole-cell recordings which was unaffected by iberiotoxin (300 nM) but abolished by glibenclamide (10 microM). 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 application of 10 microM glibenclamide. 8. These results indicate that levcromakalim 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 detrusor instability, but be of value in treating outflow obstruction.
Teramoto
N
N
University Department of Pharmacology, Oxford.
Brading
A F
AF
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D019806:Cromakalim; D004305:Dose-Response Relationship, Drug; D005260:Female; D005905:Glyburide / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D013552:Swine; D014521:Urethra / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D005905:Glyburide