title: Role of α2-adrenoceptors in electrical field stimulation-induced contraction of pig nasal mucosa and pharmacologic characterization of a novel α2C-adrenoceptor agonist.
abstract: BACKGROUND
  Blood vessels of the nasal mucosa are richly innervated by sympathetic nerves and neural mechanism is of great interest in upper respiratory tract disorders. This study was designed to determine the role of α2-adrenoceptors and, more specifically, α2C-adrenoceptors, on neurogenic sympathetic vasoconstrictor responses in pig nasal mucosa, and to define the pharmacologic profile of a novel selective α2C-adrenoreceptor agonist.
  
  
  METHODS
  Electrical field stimulation (EFS) was applied to nasal mucosa strips placed in an organ bath and attached to force displacement transducers for continuous recording of isometric tension. The affinity and functional activity of compound B for α2C-adrenoceptors were determined by binding analysis and the ability of compound B to stimulate [(35)S]GTPγS binding to the receptors. Compound B was also tested in a postjunctional α2C-adrenoreceptor bioassay.
  
  
  RESULTS
  EFS-induced contractions were partly blocked by the α2-adrenoreceptor antagonist yohimbine (41.1%) and the α2C-adrenoreceptor antagonist JP-1302 had no effect. The α2-adrenoreceptor agonist clonidine, but not compound B, exerted a significant blockade (70.6%). Compound B had high affinity (K(i) = 18 nM), produced potent agonist (EC50 = 279 nM) and good efficacy (E(max) = 73%) responses at the α2C-adrenoceptors, and displayed good functional agonist potency in the human saphenous vein α2C-adrenoreceptor bioassay (pD2 = 6.2).
  
  
  CONCLUSIONS
  (1) Neurogenic vasomotor contractility is largely regulated through an α-adrenergic mechanism; (2) pig nasal mucosa possesses post- and prejunctional α2-adrenoceptors; (3) the α2C-adrenoreceptor subtype does not seem to be involved; and (4) compound B is a novel, highly selective, and potent α2C-adrenoreceptor agonist.
authors.affiliation: In Vivo Pharmacology Department, Merck Research Laboratory, Kenilworth, New Jersey, USA.
authors.forename: Michel R
authors.initials: MR
authors.lastname: Corboz
authors.forename: Maria A
authors.initials: MA
authors.lastname: Rivelli
authors.forename: Himanshu
authors.initials: H
authors.lastname: Shah
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Boyce
authors.forename: Kevin D
authors.initials: KD
authors.lastname: McCormick
authors.forename: Richard W
authors.initials: RW
authors.lastname: Chapman
authors.forename: John C
authors.initials: JC
authors.lastname: Hunter
mesh_terms: D000166:Acridines / Q000494:pharmacology; D000322:Adrenergic Agonists / Q000494:pharmacology; D018674:Adrenergic Antagonists / Q000494:pharmacology; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D004558:Electric Stimulation; D056966:Excitation Contraction Coupling; D009297:Nasal Mucosa / Q000187:drug effects* / Q000294:innervation; D009924:Organ Culture Techniques; D010879:Piperazines / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D012501:Saphenous Vein / Q000187:drug effects; D013552:Swine; D013564:Sympathetic Nervous System; D014661:Vasoconstriction / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000166:Acridines; D000322:Adrenergic Agonists; D018674:Adrenergic Antagonists; C518829:JP-1302; D010879:Piperazines; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D003000:Clonidine