Article date: August 2010
By: SJ Rayment, T Eames, JAD Simpson, MR Dashwood, Y Henry, H Gruss, AG Acheson, JH Scholefield, VG Wilson in Volume 160, Issue 7, pages 1727-1740
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 3H‐prazosin and 3H‐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 α1‐ and α2‐adrenoceptors, and subsequent characterization with sub‐type‐selective agents, identified them as α1A‐ and α2D‐adrenoceptor sub‐types. Autoradiographic studies with 3H‐prazosin showed a positive association of α1‐adrenoceptors with immunohistochemically identified smooth muscle fibres. Anti‐α1‐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 α1‐adrenoceptor agonist. Prazosin (selective α1‐adrenoceptor antagonist) significantly reduced the magnitude of contraction to l‐erythro‐methoxamine at the highest concentration used. Both prazosin and RX811059 (a selective α2‐adrenoceptor antagonist) reduced the potency (pEC50) of clonidine.
CONCLUSIONS AND IMPLICATIONS
This study shows that both α1‐ and α2‐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.
DOI: 10.1111/j.1476-5381.2010.00842.x
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