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Eutopic Overexpression of Vasopressin V_1a Receptor in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia

Third Department of Internal Medicine (T.M., A.M., T.S., J.H., H.D., H.M., K.Y.), Gifu University School of Medicine, Gifu 500-8705; Department of Internal Medicine (H.M.), Daiyukai Hospital, Ichinomiya, Aichi 491-8551; Department of Internal Medicine (N.Y.), Matsunami General Hospital, Kasamatsu, Gifu 501-6062; First Department of Internal Medicine (T.F.), Okayama University, Okayama 700-8558; and Department of General Medicine (M.M.), Gifu Prefectural Hospital, Gifu 500-8717, Japan

Address all correspondence and requests for reprints to: Tomoatsu Mune, M.D., Ph.D., Third Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan. E-mail: mune{at}cc.gifu-u.ac.jp.

Abstract

Arginine vasopressin (AVP) stimulates cortisol secretion through its vascular type V_1a receptor in the adrenal glands, in addition to stimulating ACTH secretion through pituitary V₃ receptor. Because hyper-response of plasma cortisol to vasopressin is documented in some patients with Cushing’s syndrome due to adrenal adenoma (CS) or ACTH-independent macronodular adrenocortical hyperplasia (AIMAH), we analyzed the expression of V_1a, V₂, V₃ receptor and AVP mRNA in human adrenal tissues by quantitative competitive RT-PCR or real-time PCRs. V_1a receptor mRNA levels (ratio against glyceraldehyde 3-phosphate dehydrogenase) were 0.378 ± 0.143 (mean ± SE) in preclinical CS (n = 5) and 0.630 ± 0.072 in AIMAH (n = 4), which were significantly higher than those (0.046 ± 0.012; n = 9) in control adrenals, whereas those in overt CS (0.143 ± 0.048; n = 10) or aldosterone-producing adenomas (0.069 ± 0.018; n = 12) were similar to control adrenals. Although ectopic expression of V₂ or V₃ receptor was detected in half of AIMAH cases, the absolute levels were low. Furthermore, V_1a receptor mRNA levels in the adjacent adrenal glands (0.190 ± 0.039, n = 9) of aldosterone-producing adenomas were higher than those in control adrenals and in the corresponding tumor portions (0.079 ± 0.024). In contrast, there were no significant differences in AVP mRNA levels among these groups.

These results suggest that eutopic V_1a receptor overexpression is involved in the etiology of AIMAH and a subset of adrenal adenomas causing overt or preclinical Cushing’s syndrome. Our results imply a possible association of V_1a receptor expression with adrenal hyperplasia.

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