Role of the disulfide bridge and the C-terminal tripeptide in the antidiuretic action of vasopressin in man and the rat

Abstract

The antidiuretic action of a number of vasopressin analogues has been measured in the rat and man in water diuresis. These analogues had the following categories of structural alteration: a) substitution of -CH2CH2-(dicarba) and -SCH2-(6-monocarba) for the natural -SS- bridge between residues 1 and 6, b) changes in the nature of the C-terminal tripeptide produced by substitution of D-arginine and L-Nalpha-methylarginine for L-arginine in sequence position 8 and L-leucine for proline in position 7, and c) combinations of a and b. In addition, a highly active analogue which results when valine is substituted for glutamine in position 4 was tested. Trained, unanesthetized rats and normal human volunteers were complemented by a volunteer patient with posttraumatic diabetes insipidus (DI) in the total group of experimental subjects. The only change in the C-terminal tripeptide which was associated with a high antidiuretic action was D-Arg substitution. The meArg and Leu analogues showed low to very little activity and no signs of antidiuretic antagonist action. All of the carba analogues showed both high potency and prolongation of antidiuretic action in the following order (for both potency and duration): monocarba + 8-D-Arg greater than 4-Val + 8-D-Arg greater than 8-D-Arg alone, all in deamino form. None of the 8-D-Arg analogues had any side effects on the cardiovascular system, gut, uterus, bladder, etc. The prolongation was such that even with a DI patient refractory to the action of lysine-vasopressin and relatively resistant to deamino-[8-D-Arg]-vasopressin, water turnover could be reduced from untreated levels of 20 to 30 liters/day to less than 2 liters/day with only a single administration of deamino-6-carba-[8-D-Arg]-vasopressin as nose drops. The significance of these structural alterations in the vasopressin molecule for interaction with both antidiuretic and smooth muscle receptors was discussed.

Identification of proteins directly from tissue: in situ tryptic digestions coupled with imaging mass spectrometry

“…The calculated mass of Arg-vasopressin is 1086.44, yet experimentally it is detected in this region with a mass of 1083.44. As previously described, 26 this mass shift suggests that the C-terminus glycine is amidated and the disulfide bond is intact, the latter being further confirmed in the present study by MS/MS analysis. The calculated mass of copeptin is 4281.80 Da, yet it has been shown that this peptide is N-glycosylated 27 -29 at an asparagine residue.…”

The Renin Angiotensin System in Conscious Brattleboro Strain Rats

“…d D A V P is a synthetic A V P analogue hav ing appreciable antidiuretic potency [4,31] but lacking significant pressor activity [38]. While A V P has been shown to suppress P R A in dog kidneys perfused in vivo [16], and in isolated rat kidneys [22,37] and rat renal slices perfused or incubated in vitro [3,30], no study has shown direct intrarenal [39].…”

Aqueous-Soluble, Non-Reversible Lipid Conjugate of Salmon Calcitonin: Synthesis, Characterization and In Vivo Activity

“…For example, the replacement of the disulfide moiety in desmopressin with a sulfideYmethylene group resulted in a longer duration of activity (14). An analogue of octreotide, PTR 3173, which did not have an intra-disulfide bond, was shown to be as potent as octreotide in inhibiting forskolin-stimulated cAMP accumulation in several cell lines (15,16).…”