Investigation of the distribution and function of α‐adrenoceptors in the sheep isolated internal anal sphincter
| Autor: | V. G. Wilson, H. J. Gruss, Dashwood, J Simpson, Austin G. Acheson, S. J. Rayment, T. Eames, John H Scholefield, Y. Henry |
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| Rok vydání: | 2010 |
| Předmět: |
Agonist
medicine.medical_specialty medicine.drug_class Anal Canal Imidazoline receptor In Vitro Techniques Binding Competitive Internal anal sphincter Radioligand Assay Idazoxan Receptors Adrenergic alpha-2 Receptors Adrenergic alpha-1 Internal medicine medicine Prazosin Animals Humans Receptor Adrenergic alpha-Antagonists Pharmacology Sheep Dose-Response Relationship Drug Chemistry Antagonist Antibodies Monoclonal Adrenergic alpha-2 Receptor Antagonists Immunohistochemistry Research Papers Clonidine Endocrinology Adrenergic alpha-1 Receptor Antagonists Autoradiography Adrenergic alpha-Agonists Fecal Incontinence Muscle Contraction Protein Binding medicine.drug |
| Zdroj: | British Journal of Pharmacology. 160:1727-1740 |
| ISSN: | 1476-5381 0007-1188 |
| DOI: | 10.1111/j.1476-5381.2010.00842.x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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