Eutopic overexpression of vasopressin V1a receptor in adrenocorticotropin-independent macronodular adrenal hyperplasia

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 V-3 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, V-2, V-3 receptor and AVP mRNA in human adrenal tissues by quantitative competitive RT-PCR or real-time PCRs. Vi. 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 V-2 or V-3 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 Via 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.