Vasopressins inactivation

In some cases, receptor inactivation, e.g., of the V2 vasopressin receptor, is mediated by agonist-induced enzymatic cleavage of the GPCR. This nonendocytic proteolysis is promoted by a plasma membrane-associated metalloprotease. Proteinase-activated receptors (PARs) such as the thrombin receptor also follow a distinctly different pathway. PARs require the enzymatic cleavage of their N terminus, and the newly generated N terminus activates the receptor. Once... 

Nomura Y, Onigata K, Nagashima T et al (1997) Detection of skewed X-inactivation in two female carriers of vasopressin type 2 receptor gene mutation. J Clin Endocrinol Metab 82 3434-3437... 

PHARMACOKINETICS When vasopressin and desmopressin are given orally, they are rapidly inactivated by trypsin, which cleaves the peptide bond between amino acids 8 and 9. Inactivation by peptidases in various tissues (particularly the Uver and kidneys) results in a plasma tj of vasopressin of 17-35 minutes. Following intramuscular or subcutaneous injection, the antidiuretic effects of vasopressin last 2-8 hours. The plasma t of desmopressin has a fast component of 6.5-9 minutes and a slow component of 30-117 minutes. Only 3% and 0.15%, respectively, of intranasaUy and orally administered desmopressin is absorbed. 

The importance of both the 20-member ring and the side chain for biological function has been investigated. These investigations are still in their infancy, and only tentative conclusions can be reached. We shall consider separately the structural changes that inactivate both the oxytocin and the vasopressive effects and those that are necessary to convert oxytocin into vasopressin. 

The presence of glutamine in position 4 and asparagine in position 5 is also important because the replacement by isoglutamine or isoasparagine inactivates the hormone. In fact, isoglutamine-4-oxytocin is an inhibitor of vasopressin. 

Dhariwal 6e McCann, unpublished data, 1966). This observation indicates that intact peptide bonds are required for their activity. Carboxypeptidase failed to inactivate the FRF in one experiment. Thioglycollate splits the disulfide bridge in oxytocin and vasopressin, thus inactivating the molecules, but this treatment is without influence on LRF or hypothalamic CRF (16). Consequently, it appears likely that the chemical structures of LRF and CRF, at least with respect to the disulfide bridge, are dissimilar from that of the known neuroh3q)ophysial pol3q)eptides. 

Kidney and liver. The kidney and the liver play the major role in the clearance of oxytocin and vasopressin from the circulation. Liver extracts inactivate oxytocin by a two-stage process. The first step consists in the reduction of the disulfide bond with the simultaneous oxidation of reduced gluthathione, the reductive cleavage of oxytocin being coupled to the oxidation of NADPH as follows ... 

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