Rolipram, a Phosphodiesterase Inhibitor, in the Treatment of Two Male Patients with Congenital Nephrogenic Diabetes Insipidus
|Title:||Rolipram, a Phosphodiesterase Inhibitor, in the Treatment of Two Male Patients with Congenital Nephrogenic Diabetes Insipidus|
|Authors:||Bichet, Daniel G.; Arthus, Marie-Francoise; Ruel, Nicole; Lonergan, Michele|
|Date Published:||January 01, 1990|
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)
This molecular sequence is:
- AVP binds with AVPR2, which is already coupled to a Gs protein.
- This binding stimulates the adenylyl cyclase (AdC) enzyme complex. The stimulated AdC raises levels of the metabolic regulator, cyclic adenosine monophosphate (cAMP).
- cAMP, through a process that is not entirely clear, signals water-transporting proteins to travel to and insert themselves in the apical membrane of the principal cells of the kidney collecting duct. These proteins act as channels through which much more water than usual can pass through the apical membrane.
This is how the kidney is able to reabsorb water that flows through the collecting ducts and concentrate urine.
There is a breed of mice that have hereditary NDI; however their NDI is not X-linked (i.e. the gene that is responsible for their NDI is not carried on the X chromosome). Also, the molecular mechanism of their NDI differs from X-linked NDI in that, due to a high level of activity of a molecular complex called cAMP-phospodiesterase, the mice are unable to accumulate sufficient amounts of cAMP to signal the water-transporting proteins to travel to and insert themselves in the apical membrane of the collecting duct cells.
Researchers found that two inhibitors of cAMP-phosphodiesterase, Rolipram and Cilostamide, so effectively inhibited cAMP-phosphodiesterase that cAMP was able to accumulate in response to AVP. Mice injected with Rolipram showed more concentrated urine and a correction of their polyuria. Bichet, et al., treated two male X-linked NDI patients with Rolipram, but they showed no improvement in any of the variables tested by the researchers. This suggested that the mouse defect in cAMP breakdown is not present in humans with X-linked NDI.