Epinephrine and dDAVP Administration in Patients with Congenital Nephrogenic Diabetes Insipidus. Evidence for a pre-cyclic AMP V2 Receptor Defective Mechanism

Title: Epinephrine and dDAVP Administration in Patients with Congenital Nephrogenic Diabetes Insipidus. Evidence for a pre-cyclic AMP V2 Receptor Defective Mechanism
Authors: Bichet, Daniel G.; Razi, Mohammad; Arthus, Marie-Francoise; Lonergan, Michele; Tittley, Pauline; Smiley, Robert K.; Rock, PhD, MD, FRCP, Gail; Hirsch, David J.
Publisher: Kidney International
Date Published: November 01, 1989
Reference Number: 428
We recently showed that the administration of the antidiuretic V2 specific agonist, 1-desamino[8-D-arginine]vasopressin (dDAVP), to seven male patients with congenital nephrogenic diabetes insipidus (CNDI) did not cause a decrease in blood pressure nor an increase in plasma renin activity or factor VIIIc or von Willebrand factor release. In normal subjects, plasma renin activity, coagulation factors and plasma cyclic AMP are stimulated not only by dDAVP but also by the administration of epinephrine. In the present study, we measured tissue plasminogen activator (activity and antigenicity), von Willebrand factor multimers, plasma and urinary cyclic AMP concentrations following dDAVP or epinephrine administration. We infused epinephrine into three male patients with CNDI. Factor VIIIc and tissue plasminogen activator augmented by 75 to 100% and von Willebrand Factor multimers were increased; plasma renin activity and plasma cyclic AMP concentration increased by 200%. None of these values changed when the same subjects as well as eleven other male patients with CNDI received dDAVP. Furthermore, dDAVP administration increased plasma cyclic AMP concentrations in normal subjects, but not in 14 male patients with CNDI. These results demonstrate the specificity of the extrarenal V2 receptor defect expressed in our patients. The lack of a plasma cyclic AMP response to the administration of dDAVP would suggest an altered pre-cyclic AMP stimulation mechanism.
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

The antidiuretic hormone, arginine vasopressin (AVP) interacts with two types of receptors: the vasopressin-1 receptor (V1R) and the vasopressin-2 receptor (V2R). When AVP binds with V1R it initiates a molecular sequence that leads to constriction of blood cells and the release of prostaglandin E2. When AVP binds with V2Rs located in the principal cells of the kidney collecting duct, it initiates a molecular sequence that allows the kidney to concentrate urine and reabsorb water flowing through the collecting ducts.

Congenital nephrogenic diabetes insipidus (NDI) is a rare X-linked disorder characterized by the kidney's inability to respond to AVP. Thus, the kidney cannot concentrate urine or reabsorb water through the kidney collecting duct. Ordinarily, AVP binds with V2R, which is coupled to a G protein in the collecting duct cell membrane. This binding stimulates a rise in the activity of the enzyme, adenylyl cyclase (AC). AC then instigates a rise in the concentration of cAMP. cAMP then induces water-transporting proteins called aquaporin-2s (AQP2s) to be transported from within the cell to the cell membrane where it is inserted to make the membrane more water permeable. It is the increased permeability of the membrane that lets the kidney concentrate urine and reabsorb water through the membranes.

The fact that NDI patients do not respond to AVP or DDAVP indicated to researchers that the defect that is responsible for NDI might lie somewhere within the molecular sequence (described above) that leads to urine concentration and water reabsorption.

The other area in the body beside the kidney that healthy people show a response to DDAVP is the blood. DDAVP causes a decrease in blood pressure and the plasma activity level of the enzyme, renin. It also causes a release of two blood coagulation factors called Factor VIIIc and von Willebrand factor. When NDI patients are administered doses of DDAVP, they show no such responses. Since the responses displayed by the healthy people could only occur if mediated by V2Rs, some researchers have suggested that V2Rs exist outside, as well as inside, the kidney. If this is so, then NDI patients seem to have a general V2R defect that prevents it from binding with AVP no matter where it was located. This points to defective V2Rs as the possible cause of X-linked NDI.

To further substantiate this notion, Bichet, et al., designed a study that compared the responses of normal people, NDI patients, and carriers of the NDI-causing gene to infusions of DDAVP and epinephrine, a hormone known to stimulate the same blood coagulation factors as DDAVP. The variables they measured that would indicate a response to DDAVP were levels of tissue plasminogen activator, antigenicity, von Willebrand factor, factor VIIIc, and the plasma and urinary concentrations of cAMP.

The researchers reasoned that if the NDI patients responded to epinephrine by increased levels of the above variables, but showed no such increases in response to DDAVP, this would suggest that the defect causing NDI would exist somewhere in the molecular sequence before cAMP is elevated.

The authors infused three NDI patients with epinephrine. The patients showed a positive response. Their factor VIllc and tissue plasminogen activator was increased by 75 to 100%; their von Willebrand factor increased; their plasma renin activity and plasma cAMP concentration increased by 200%. None of these factors increased when these same NDI patients were infused with DDAVP. In fact, none of the 14 NDI patients showed an increase in any of these factors when infused with DDAVP, whereas all the healthy subjects did. The NDI carrier group responded about half as strongly to DDAVP as did the control group.

These results suggested to the researchers that the NDI patients' defective plasma cAMP response to DDAVP was specific to DDAVP and AVP since their plasma cAMP increased with epinephrine. Being specific to DDAVP and AVP indicates the cause of NDI lies in either defective V2Rs, faulty G proteins, or the adenylyl cyclase phase of the sequence. The authors think the most likely candidate is defective V2Rs caused by mutated V2R genes.

These results have been confirmed by the identification of AVPR2 mutations in patients with X-linked nephrogenic diabetes insipidus (for review see: Bichet DG, Fujiwara TM. 2001 Nephrogenic diabetes insipidus. In: Scriver CR, Beaudet AL, Sly WS, Vallee D, Childs B, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 4181-4204).