Expression and Functional Analysis of Dopamine Receptor Subtype 2 and Somatostatin Receptor Subtypes in Canine Cushing’s Disease

• Published in: Endocrinology (Philadelphia) 2008-09, Vol.149 (9), p.4357-4366
• Main Authors: de Bruin, C, Hanson, J. M, Meij, B. P, Kooistra, H. S, Waaijers, A. M, Uitterlinden, P, Lamberts, S. W. J, Hofland, L. J
• Format: Article
• Language: English
• Subjects: ACTH-Secreting Pituitary Adenoma - genetics; ACTH-Secreting Pituitary Adenoma - metabolism; ACTH-Secreting Pituitary Adenoma - pathology; Adenoma; Adenoma - genetics; Adenoma - metabolism; Adenoma - pathology; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Adrenocorticotropic hormone; Agonists; Analogs; Animals; Biological and medical sciences; Cells, Cultured; Dexamethasone - pharmacology; Dog Diseases - genetics; Dog Diseases - metabolism; Dog Diseases - pathology; Dogs; Dopamine; Dopamine D2 receptors; Effectiveness; Endocrinopathies; Female; Follow-Up Studies; Functional analysis; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic - drug effects; Health services; Immunohistochemistry; Male; Medical sciences; Medical treatment; Nervous system diseases; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Octreotide; Pituitary (anterior); Pituitary ACTH Hypersecretion - genetics; Pituitary ACTH Hypersecretion - metabolism; Pituitary ACTH Hypersecretion - pathology; Pituitary ACTH Hypersecretion - veterinary; Protein Isoforms - genetics; Protein Isoforms - metabolism; Receptors; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D2 - metabolism; Receptors, Dopamine D2 - physiology; Receptors, Somatostatin - genetics; Receptors, Somatostatin - metabolism; Receptors, Somatostatin - physiology; RNA, Messenger - metabolism; Somatostatin; Somatostatin receptors; Tumors; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2008-0244

Cushing’s disease (CD) is a severe disorder characterized by chronic hypercortisolism due to an ACTH-secreting pituitary adenoma. Transsphenoidal adenomectomy is the treatment of choice in humans with CD, but recurrences occur frequently. Finding an effective and safe medical treatment for CD may improve long-term clinical outcome. The recent demonstration of expression of somatostatin receptor subtypes (mainly sst5) and dopamine receptor subtype 2 (D2) in human corticotroph adenomas offers the possibility for medical treatment of CD with novel somatostatin analogs and dopamine agonists. Investigation of the effects of these drugs is hampered by the low incidence of CD in humans. Interestingly, CD is a frequent disorder in dogs with striking clinical similarities with CD in humans. Therefore, we investigated the expression and functional role of D2 and somatostatin receptors in corticotroph adenoma cells from 13 dogs with active CD that underwent therapeutic hypophysectomy and normal anterior pituitary cells from five dogs. Quantitative RT-PCR and immunohistochemistry revealed that both in CD and normal anterior pituitary, sst2 was the predominant receptor subtype expressed, whereas D2 was modestly expressed and sst5 was expressed only at very low levels. In primary cultures of canine adenomas (n = 7), the sst2-preferring agonist octreotide also showed the strongest ACTH-suppressive effects. In conclusion, canine corticotroph adenomas provide an interesting model to study CD, but differences in somatostatin and dopamine receptor expression between humans and dogs should be taken into account when using dogs with CD as a model to evaluate efficacy of novel somatostatin analogs and dopamine agonists for human CD.