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Investigation of the distribution and function of α‐adrenoceptors in the sheep isolated internal anal sphincter
Author(s) -
Rayment SJ,
Eames T,
Simpson JAD,
Dashwood MR,
Henry Y,
Gruss H,
Acheson AG,
Scholefield JH,
Wilson VG
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00842.x
Subject(s) - imidazoline receptor , prazosin , methoxamine , endocrinology , medicine , chemistry , agonist , antagonist , receptor , isometric exercise , contraction (grammar) , internal anal sphincter , adrenergic receptor , biology , pharmacology , rectum , anal canal
BACKGROUND AND PURPOSE We have investigated the distribution of α‐adrenoceptors in sheep internal anal sphincter (IAS), as a model for the human tissue, and evaluated various imidazoline derivatives for potential treatment of faecal incontinence. EXPERIMENTAL APPROACH Saturation and competition binding with 3 H‐prazosin and 3 H‐RX821002 were used to confirm the presence and density of α‐adrenoceptors in sheep IAS, and the affinity of imidazoline compounds at these receptors. A combination of in vitro receptor autoradiography and immunohistochemistry was used to investigate the regional distribution of binding sites. Contractile activity of imidazoline‐based compounds on sheep IAS was assessed by isometric tension recording. KEY RESULTS Saturation binding confirmed the presence of both α 1 ‐ and α 2 ‐adrenoceptors, and subsequent characterization with sub‐type‐selective agents, identified them as α 1A ‐ and α 2D ‐adrenoceptor sub‐types. Autoradiographic studies with 3 H‐prazosin showed a positive association of α 1 ‐adrenoceptors with immunohistochemically identified smooth muscle fibres. Anti‐α 1 ‐adrenoceptor immunohistochemistry revealed similar distributions of the receptor in sheep and human IAS. The imidazoline compounds caused concentration‐dependent contractions of the anal sphincter, but the maximum responses were less than those elicited by l ‐erythro‐methoxamine, a standard non‐imidazoline α 1 ‐adrenoceptor agonist. Prazosin (selective α 1 ‐adrenoceptor antagonist) significantly reduced the magnitude of contraction to l ‐erythro‐methoxamine at the highest concentration used. Both prazosin and RX811059 (a selective α 2 ‐adrenoceptor antagonist) reduced the potency (pEC 50 ) of clonidine. CONCLUSIONS AND IMPLICATIONS This study shows that both α 1 ‐ and α 2 ‐adrenoceptors are expressed in the sheep IAS, and contribute (perhaps synergistically) to contractions elicited by various imidazoline derivatives. These agents may prove useful in the treatment of faecal incontinence.