title: Dual effects of α2 -adrenoceptors in modulating myogenic tone in sheep isolated internal anal sphincter.
abstract: BACKGROUND
  The role of α-adrenoceptors in promoting continence through modulation of sphincter tone has focused primarily on the effects of α1 -adrenoceptors. We have used three clinically available agents, which are selective for α2 -adrenoceptors, to investigate their role in contractile and neurogenic responses on the internal anal sphincter (IAS).
  
  
  METHODS
  IAS strips, which had spontaneously generated tone, were used to investigate the contractile effect of lofexidine, brimonidine, and dexmedetomidine on muscle tone in the presence or absence of subtype selective antagonists. The effect of brimonidine on the magnitude and time course of neurogenic responses generated by electrical field stimulation (EFS) was also examined. The affinity of test compounds at α1 - and α2 -adrenoceptors was established by competition binding with [3H]-prazosin and [3H]-RX821002.
  
  
  RESULTS
  All agonists caused concentration-dependent contraction of the IAS and lofexidine demonstrated an enantiomeric difference in potency with a 10-fold difference between the (-) and (+) isomers. Responses to lofexidine and dexmedetomidine were inhibited in the presence of the α1 -adrenoceptor selective antagonist prazosin, but not in the presence of RX811059 (α2 -adrenoceptor selective antagonist); brimonidine responses were inhibited by RX811059 and, to a lesser extent, by prazosin. Brimonidine affected both magnitude and duration of neurogenic responses, which was reversed in the presence of RX811059.
  
  
  CONCLUSIONS
  We conclude that α2 -adrenoceptors can mediate contraction of IAS, although this effect is most evident with efficacious imidazoline agonists rather than the most selective ligand. In addition, this receptor subtype can directly inhibit noradrenergic contractile responses to EFS and, indirectly, enhance nitrergic relaxatory responses.
authors.affiliation: Division of GI Surgery, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Rayment
authors.forename: J A D
authors.initials: JA
authors.lastname: Simpson
authors.forename: T
authors.initials: T
authors.lastname: Eames
authors.forename: A G
authors.initials: AG
authors.lastname: Acheson
authors.forename: M R
authors.initials: MR
authors.lastname: Dashwood
authors.forename: Y
authors.initials: Y
authors.lastname: Henry
authors.forename: H
authors.initials: H
authors.lastname: Gruss
authors.forename: J H
authors.initials: JH
authors.lastname: Scholefield
authors.forename: V G
authors.initials: VG
authors.lastname: Wilson
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D058647:Adrenergic alpha-2 Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*; D001003:Anal Canal / Q000187:drug effects* / Q000502:physiology*; D000818:Animals; D000068438:Brimonidine Tartrate; D003000:Clonidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D020927:Dexmedetomidine / Q000378:metabolism / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D011224:Prazosin / Q000032:analysis / Q000494:pharmacology; D011810:Quinoxalines / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D012756:Sheep; D046509:Tissue Culture Techniques
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D058647:Adrenergic alpha-2 Receptor Agonists; D011810:Quinoxalines; D011942:Receptors, Adrenergic, alpha; D000068438:Brimonidine Tartrate; D020927:Dexmedetomidine; D003000:Clonidine; C025655:lofexidine; D011224:Prazosin
keywords: fecal incontinence; imidazoline; radioligand binding