Demonstration of a defect in the formation of adenosine 3',5'-monophosphate in vasopressin-resistant diabetes insipidus.

Abstract

Extract: Previous studies had indicated that the effects of vasopressin to increase the permeability of collecting ducts to water and to produce a concentrated urine are mediated through adenosine 3′, 5′-monophosphate (cyclic AMP). An investigation was performed to determine whether the lack of response to vasopressin in nephrogenic diabetes insipidus could result from an abnormality in the formation of cyclic AMP. The influence of vasopressin was compared in four water-loaded normal subjects, one patient with vasopressin deficiency, and three patients with nephrogenic diabetes insipidus. Serum and urine osmolality, inulin clearance, and cyclic AMP in urine were determined while 5% dextrose and water was infused at a constant rate before, during, and after administration of vasopressin for 1 hr. Vasopressin given intravenously for 1 hr significantly increased the mean rate of excretion of cyclic AMP in urine from a range of from 1.7 to 3.1 nmol/min before treatment to a range of from 4.7 to 8.9 nmol/min after treatment in the normal subjects and the patient with vasopressin deficiency. There were associated mean increases in urine osmolality from a range of from 39 to 119 mOsm/kg to a range of from 568 to 996 mOsm/kg. In contrast, mean cyclic AMP in urine varied from 0.7 to 1.5 nmol/min and mean urine osmolality varied from 47 to 68 mOsm/kg in the patients with nephrogenic diabetes insipidus and did not change after vasopressin. The findings are interpreted to mean that there is a defect in the adenylate cyclase system in nephrogenic diabetes insipidus. It is not known whether there is an abnormality of the receptor, the enzyme, or both or if there is an associated abnormality of the renal tubules to respond to cyclic AMP. Speculation: The results show that patients with nephrogenic diabetes insipidus do not increase levels of cyclic AMP in urine or concentrate their urine in response to vasopressin. It is proposed that there is a defect in the adenylate cyclase system in these patients which accounts for their lack of response to antidiuretic hormone.