title: Pharmacological evidence that tetraethylammonium-sensitive, iberiotoxin-insensitive K+ channels function as a negative feedback element for sympathetic neurotransmission by suppressing omega-conotoxin-GVIA-insensitive Ca2+ channels in the relaxation of rabbit facial vein.
abstract: The facial vein isolated from various species relaxes in response to electrical field stimulation (EFS). EFS-elicited relaxation of the facial vein is mediated through the release of noradrenaline (NA) from sympathetic nerve endings and the subsequent activation of smooth muscle beta-adrenoceptors. The release of NA from sympathetic nerve endings in arterial tissues requires transmembrane Ca2+ influx, mediated predominantly by voltage-gated N-type Ca2+ channels. The present pharmaco-mechanical study was undertaken to determine whether the N-type channel is the exclusive pre-junctional Ca2+ channel mediating NA release from sympathetic nerve endings in the rabbit facial vein. Possible roles of K+ channels in the sympathetic neurotransmission were also examined, especially focusing on the contribution of voltage-dependent, Ca2+-activated K+ (BKCa) channels. An isolated ring preparation of the rabbit facial vein exhibited intrinsic myogenic tone which lasted for several hours when stretched. EFS produced frequency-dependent (0.25-2 Hz) relaxation in this preparation. EFS-elicited relaxation was abolished by tetrodotoxin (TTX, 1 microM), guanethidine (5 microM) or propranolol (1 microM), indicating that NA released from sympathetic nerve endings was mediating the relaxant response. NA-mediated neurogenic relaxation was almost eliminated by omega-conotoxin-GVIA (1 microM), an N-type Ca2+ channel blocker. On the other hand, tetraethylammonium (TEA, 2 mM) strongly potentiated EFS-elicited relaxation without affecting the relaxation induced by exogenously applied NA. This potentiation by TEA was not profoundly diminished by omega-conotoxin-GVIA (1 microM) alone or omega-conotoxin-GVIA (1 microM) plus omega-agatoxin IVA (10 nM, P-type channel blocker), but was almost abolished by omega-conotoxin-GVIA (1 microM) plus omega-agatoxin IVA (10 nM) plus omega-conotoxin-MVIIC (3 microM, N-, P- and Q-type channel blocker). The potentiating effect of TEA was not mimicked by iberiotoxin (100 nM) or charybdotoxin (3 microM), both of which block BKCa channels. These findings suggest that pre-junctional N-type Ca2+ channels play the predominant role in the sympathetic nerve transmission in the rabbit facial vein, as in peripheral arterial vascular beds. In addition, Ca2+ channels resistant to 1 microM omega-conotoxin-GVIA, most probably Q-type channels, appear to be present at the sympathetic nerve endings in the rabbit facial vein and contribute substantially to the regulation of NA release from the nerve endings. Prejunctional K+ channels, sensitive to TEA but pharmacologically distinct from iberiotoxin-sensitive BKCa channels, seem to be functionally coupled intimately with the omega-conotoxin-GVIA-resistant Ca2+ channels, and thus function as a negative feedback element in sympathetic neurotransmission in the rabbit facial vein.
authors.affiliation: Department of Pharmacology, Toho University School of Pharmaceutical Sciences, 2-2-1 Miyama, Funabashi-City, Chiba 274-8510, Japan. yotanaka@phar.toho-u.ac.jp
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Aya
authors.initials: A
authors.lastname: Akutsu
authors.forename: Hikaru
authors.initials: H
authors.lastname: Tanaka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Horinouchi
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Tsuru
authors.forename: Katsuo
authors.initials: K
authors.lastname: Koike
authors.forename: Koki
authors.initials: K
authors.lastname: Shigenobu
mesh_terms: D000320:Adrenergic Fibers / Q000187:drug effects / Q000502:physiology; D000818:Animals; D020907:Calcium Channels, Q-Type / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005145:Face / Q000098:blood supply / Q000502:physiology; D025461:Feedback, Physiological / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D011817:Rabbits; D019789:Tetraethylammonium / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014680:Veins / Q000187:drug effects / Q000502:physiology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology*
chemical_list: D020907:Calcium Channels, Q-Type; D010455:Peptides; D015221:Potassium Channels; D019789:Tetraethylammonium; C064719:iberiotoxin; D020866:omega-Conotoxin GVIA