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Abnormal Adrenal and Vascular Responses to Vasopressin Mediated by a V₁-Vasopressin Receptor in a Patient with Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia, Cushing’s Syndrome, and Orthostatic Hypotension¹

Divisions of Endocrinology (A.L., J.T., P.H.) and Internal Medicine (J.R.C, E.S.), Research Center (A.L., J.T., J.R.C., P.H.) Hôtel-Dieu de Montréal, Montréal H2W 1T8; Multidisciplinary Research Group on Hypertension (R.M.T., L.Y.D., R.L., E.L.S.), Institut de Recherches Cliniques de Montréal, Montréal H2W 1R7; and Department of Medicine (A.L., J.T., R.M.T., L.Y.D., R.L., J.R.C., E.L.S., P.H.), Université de Montréal, Montréal, Quebec, Canada

Address all correspondence and requests for reprints to: Dr. André Lacroix, Centre de Recherche, Hôtel-Dieu de Montréal, 3850 St-Urbain, Montréal (Québec) H2W 1T8, Canada.

The elucidation of gastric inhibitory polypeptide-dependent Cushing’s syndrome suggested that ectopic expression or increased responsiveness of other adrenal hormone receptors may underlie ACTH-independent macronodular adrenal hyperplasia (AIMAH) or adrenocortical tumors. We studied a 36-yr-old woman with Cushing’s syndrome, AIMAH, and orthostatic hypotension. During upright posture, cortisol and aldosterone were stimulated despite suppression of ACTH and renin. Arginine vasopressin (AVP, 10 U im), under dexamethasone suppression, increased plasma cortisol (3.4-fold), aldosterone (67-fold), and androgens in this patient but not in controls. ACTH 1–24, but not desmopressin acetate, angiotensin II, isoproterenol, or other hormones stimulated steroidogenesis in vivo. Plasma AVP was undetectable initially and increased suboptimally during posture tests after bilateral adrenalectomy. AVP stimulated cortisol production more in dispersed cells from the AIMAH than from a normal adult adrenal (424 vs. 135% at 10 nmol/L). Adrenal V₁-AVP receptor presence and mediation of response were shown by RT-PCR and by binding and [Ca⁺⁺]_i studies. Post adrenalectomy, orthostatic hypotension persisted; a prolonged vasoconstrictive response to AVP was found in vitro in the patient’s sc small arteries. We propose that altered adrenal and vascular responses of the V₁-AVP receptor-effector pathway underlie this new syndrome.

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