title: Effect of a novel BKCa opener on BKCa currents and contractility of the rabbit corpus cavernosum.
abstract: Large-conductance Ca(2+)-activated K(+) (BKCa) channels are thought to play a key role in the regulation of corpus cavernosum smooth muscle (CCSM) excitability. Few BKCa channel openers have been accepted for clinical development. The effect of the novel BKCa channel opener GoSlo-SR5-130 on electrical activity in isolated rabbit CCSM cells and mechanical activity in strips of rabbit CCSM was examined. Single-channel currents were observed in inside-out patches. These channels were sensitive to Ca(2+), blocked by penitrem A, and had a conductance of 291 ± 20 pS (n = 7). In the presence of GoSlo-SR5-130, the number of open BKCa channels increased. Using voltage-ramp protocols, GoSlo-SR5-130 caused currents to activate at more negative potentials in a concentration-dependent manner, shifting the half-maximal activation voltage potential to the left on the voltage axis. Therefore, BKCa channels were open within the physiological range of membrane potentials in the presence of GoSlo-SR5-130. GoSlo-SR5-130 also resulted in an increase in the activity of spontaneous transient outward currents in myocytes isolated from CCSM, and this effect was reversed by iberiotoxin. In current-clamp mode, GoSlo-SR5-130 hyperpolarized the cell membrane. Isometric tension recording of strips of rabbit corpus cavernosum showed that GoSlo-SR5-130 inhibited spontaneous contractions in a concentration-dependent manner. This effect was reversed in the presence of iberiotoxin, suggesting that GoSlo-SR5-130 exerts its effect through BKCa channels. These findings suggest that GoSlo-SR5-130 is an effective tool for the study of BKCa channels and that these channels can modulate CCSM activity and are possible targets for the treatment of erectile dysfunction.
authors.affiliation: Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Ireland.
authors.forename: K I
authors.initials: KI
authors.lastname: Hannigan
authors.affiliation: Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Ireland.
authors.forename: R J
authors.initials: RJ
authors.lastname: Large
authors.affiliation: Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Ireland.
authors.forename: E
authors.initials: E
authors.lastname: Bradley
authors.affiliation: Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Ireland.
authors.forename: M A
authors.initials: MA
authors.lastname: Hollywood
authors.affiliation: Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Ireland.
authors.forename: G P
authors.initials: GP
authors.lastname: Sergeant
authors.affiliation: Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Ireland.
authors.forename: N G
authors.initials: NG
authors.lastname: McHale
authors.affiliation: Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Ireland keith.thornbury@dkit.ie.
authors.forename: K D
authors.initials: KD
authors.lastname: Thornbury
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015640:Ion Channel Gating / Q000187:drug effects*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000098:blood supply*; D011188:Potassium / Q000378:metabolism*; D011817:Rabbits; D013451:Sulfonic Acids / Q000494:pharmacology*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D000880:Anthraquinones; C000607770:GoSlo-SR-5-130; D051036:Large-Conductance Calcium-Activated Potassium Channels; D013451:Sulfonic Acids; D014662:Vasoconstrictor Agents; D011188:Potassium
keywords: corpus cavernosum; erectile dysfunction; large-conductance Ca2+-activated K+ channel; patch clamp; smooth muscle