Laboratory Investigation

Kidney International (1975) 8, 292–302; doi:10.1038/ki.1975.116

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

J H Cort, O Schück, J Str caroníbrná, J S caronkopková, K Jos caront and J L Mulder

Laboratory for Peptide Biology, Institute of Organic Chemistry and Biochemistry, Academy of Sciences, and Department of Clinical Pharmacology, Institute of Clinical and Experimental Medicine, Prague, Czechoslovakia; and Ferring, Ltd., Malmö, Sweden

Correspondence: Dr J H Cort, Academy of Sciences, Budejovicka 1083, CS-142-20 Prague, Czechoslovakia.

Received 8 January 1975; Revised 18 April 1975.

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Abstract

Role of the disulfide bridge and the C-terminal tripeptide in the antidiuretic action of vasopressin in man and the rat. 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- (di-carba) 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 tripep-tide 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 > 4-Val + 8-D-Arg > 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 <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.

Le rôle du pont disulfure et du tripeptide C terminal dans l'action antidiurétique de la vasopressine chez l'homme et le rat. L'action antidiurétique de divers analogues de la vasopressine a été mesurée chez le rat et l'homme en situation de diurèse aqueuse. Ces analogues ont les modifications structurales suivantes: a) substitution de ponts -CH2CH2- (dicarbone) et -SCH2- (monocarbone) au pont disulfure naturel entre les résidus 1 et 6, b) altérations de la nature du tripeptide C terminal obtenues par substitution de D-arginine et de L-Nalpha-methylarginine à la L-arginine en position 8 dans la séquence et de la L-leucine à la proline en position 7, c) combinaison de a et b. De plus, un analogue très actif, obtenu par substitution de la valine à la glutamine en position 4, a été essayé. Des rats en traînés, non anesthésiés, des humains volontaires et un malade, volontaire, atteint de diabète insipide ont constitué le groupe expérimental. La seule modification du tripeptide C terminal qui permet une action antidiurétique importante est la substitution de D-arginine à la L-arginine. Les analogues methyl arginine et leucine ont une très faible activité et n'ont pas d'effet antagoniste. Tous les analogues où le pont disulfure est remplacé par une structure dicarbone ou monocarbone ont une action antidiurétique puissante et efficace dans l'ordre décroissant (à la fois pour l'intensité et la durée) suivant: monocarbone + 8-D-Arg > 4-Val + 8-D Arg > 8-D-Arg seul, tous sous a forme désanimée. Les analogues 8-D-Arg n'ont pas d'effets secondaires sur le système cardiovasculaire, l'intestin, l'utérus, la vessie etc. La prolongation de l'effet est telle que chez un malade atteint de diabète insipide réfractaire à la lysine vasopressine et relativement résistant à la 8-D-Arg-Vasopressine, le renouvellement de l'eau a pu être réduit de 20 à 30 litres par jour avant traitement à moins de 2 litres par jour par une seule administration de desamino-b-monocarbone-[8-D-Arg]-vasopressine sous forme de gouttes nasales. La signification de ces modifications structurales de la molécule de vasopressine en ce qui concerne l'interaction avec les récepteurs antidiurétiques et musculaires lisses est discutée.

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References

  1. Thorn NA: The influence of the neurohypophysial hormones and similar polypeptides on the kidneys, in Handbuch der Experimentellen Pharmakologie, edited by Berde B, New York, Springer-Verlag, 1968, vol. 23, pp. 372–442
  2. Saameli K: The circulatory actions of neurohypophysial hormones and similar polypeptides. in Handbuch der Experiment-ellen Pharmakologie, edited by Berde B, New York, Springer-Verlag, 1968, vol. 23, pp. 545–612
  3. Lauson HD: Metabolism of antidiuretic hormones. Am J Med 42:713–744, 1967 | Article | PubMed | ChemPort |
  4. Cort JH, Albrecht I, Nováková J, Mulder JL, Jos caront K: Regional and systemic haemodynamic effects of some vasopressins. Eur J Clin Invest 5:165–175, 1975
  5. Ginsburg M: Production, release, transportation and elimination of the neurohypophysial hormones, in Handbuch der Experimentellen Pharmakologie, edited by Berde B, New York, Springer-Verlag, 1968, vol. 23, pp. 286–371
  6. Koida M, Glass JD, Schwartz IL, Walter R: Mechanisms of inactivation of oxytocin by rat kidney enzymes. Endocrinology 88:633–643, 1971
  7. Marks N, Abrash L, Walter R: Degradation of neurohypophysial hormones by brain extracts and purified brain enzymes. Proc Soc Exp Biol Med 142:455–460, 1973 | PubMed | ChemPort |
  8. Rychlík I: Inactivation of oxytocin and vasopressin by tissue enzymes: A basis for the design of analogues, in Proc 2nd Int Pharmacol Meet, edited by Rudinger J, Oxford, Pergamon Press, 1963, vol. 10, pp. 153–162
  9. Walter R, Bowman RH: Mechanisms of inactivation of vasopressin and oxytocin by the isolated, perfused rat kidney. Endocrinology 92:189–193, 1973 | PubMed | ChemPort |
  10. Walter R, Griffiths EC, Hooper KC: Production of MSH-release-inhibiting hormone by a particulate fraction of hypothalamus: mechanisms of oxytocin inactivation. Brain Res 60:449–457, 1973
  11. Vávra I, Machová A, Holec caronek V, Cort JH, Zaoral M, S caronorm F: Effect of aiynthetic analogue of vasopressin in animals and in patients with diabetes insipidus. Lancet 1:948–952, 1968
  12. Vávra I, Machová A, Krejc caroní I: Antidiuretic action of 1-deamino-[8-D-arginine]-vasopressin in unanesthetized rats. J Pharmacol Exp Ther 188:241–247, 1974 | PubMed | ChemPort |
  13. Zaoral M, Kolc J, S caronorm F: Synthesis of l-deamino-8-D-gamma-aminobutyrine-vasopressin, 1 -deamino-8-D-lysine-vasopressin and l-deamino-8-D-arginine-vasopressin. Collec Czech Chem Commun 32:1250–1257, 1967
  14. Andersson KE, Arner B: Effects of DDAVP, a synthetic analogue of vasopressin, in patients with cranial diabetes insipidus. Acta Med Scand 192:21–27, 1972
  15. Edwards CRW, Kitau MJ, Chard T, Besser GM: Vasopressin analogue DDAVP in diabetes insipidus: Clinical and laboratory studies. Br Med J 3:375–378, 1973
  16. Sawyer WH, Acosta M, Balaspiri L, Judd J, Manning M: Structural changes in the arginine-vasopressin molecule that enhance antidiuretic activity and specificity. Endocrinology 94:1106–1115, 1974 | ChemPort |
  17. Jos caront K, Procházka Z, Cort JH, Barth T, S caronkopková J, Prusiksík Z, S caronorm F: Synthesis and some biological activities of analogues of deaminovasopressin with the disulphide bridge altered to a thioether bridge. Collec Czech Chem Commun 39:2835–2856, 1974
  18. Hase S, Sakakibara S, Wahrenburg M, Kirchberger M, Schwartz IL, Walter R: 1, 6-Aminosuberic acid analogs of lysine- and arginine-vasopressin and -vasotocin: Synthesis and biological properties. J Am Chem Soc 94:3590–3600, 1972
  19. Burn JH, Finney DJ, Goodwin LG: Biological Standardization (2nd ed). London, Oxford University Press, 1950
  20. Brod J, Sirota JH: The renal clearance of endogenous creatinine in man. J Clin Invest 27:645–654, 1948
  21. Str caroníbrná J, Schuck O: The problem of determining the site of action of diuretics on tubular sodium reabsorption in man. Int J Clin Pharmacol 6:504–513, 1968
  22. Plis caronka V, Rychlík I: Determination of antidiuretic activity in the rat for structural analogues of the neurohypophysial hormones. Acta Endocrinol 34:129–140, 1967
  23. Berde B, Boissonas RA: Basic pharmacological properties of synthetic analogues and homologues of the neurohypophysial hormones, in Handbuch der Experimentellen Pharmakologie, edited by Berde B, New York, Springer-Verlag, 1968, vol. 23, pp. 802–870
  24. Schröder E, Lübke K: The Peptides, Vol II, Synthesis, Occurrence and Action of Biologically Active Polypeptides, New York, Academic Press Inc, 1966
  25. Sawyer WH, Acosta M, Manning M: Structural changes in the arginine vasopressin molecule that prolong its antidiuretic action. Endocrinology 95:140–149, 1974 | PubMed | ISI | ChemPort |
  26. Pullman B, Pullman A: Molecular orbital calculations on the conformation of amino acid residues of proteins, in Advances in Protein Chemistry, edited by Anfinsen CB, Edsall JT, Richards FM, New York, Academic Press Inc, 1974, vol. 28, pp. 347–526
  27. Barth T, Krejc caroní I, Kupková B, Jos caront K: Pharmacology of cyclic analogues of deamino-oxytocin not containing a disulphide bond (carba analogues). Eur J Pharmacol 24:183–188, 1973
  28. Barth T, Krejcí I, Vane caronc caronková J, Jos caront K, Rychlík I: Pro-longed action of deamino-carba analogues of oxytocin on the rat uterus in vivo. Eur J Pharmacol 25:67–70, 1974
  29. Cort JH, S caronkopková J, Sedlákovaá E: Chemical structure and mechanisms of natriuretic action of natural and synthetic neurohypophysial peptides, in Recent Advances in Renal Physiology, edited by Wirz H, Spinelli F, Basel, S. Karger-Verlag, 1972, pp. 121–129
  30. Cort JH, S caronkopková J, Sedláková E: The relation of neurohypophysial peptide structure to sodium transport in kidney and other tissues, in Peptides-1972, edited by Hanson H, Jakubke HD, Amsterdam, North Holland Pub Co, 1973, pp. 458–462
  31. Fric caron I, Kodic caronek M, Jos caront K, Bláha K: Chiroptical properties of carba-analogues of oxytocin: Conformational considerations. Collec Czech Chem Commun 39:1271–1289, 1974
  32. Fric caron I, Kodic caronek M, Procházka Z, Jos caront K, Bláha K: Synthesis and circular dichroism of deamino-1-carba-oxytocin with modifications of the amino-acid residue in position 2. Collec Czech Chem Commun 39:1290–1302, 1974
  33. Aronson AS, Andersson KE, Bergstrand CG, Mulder JL: Treatment of diabetes insipidus in children with DDAVP, a synthetic analogue of vasopressin. Acta Paediatr Scand 62:133–140, 1973
  34. Kendall AR: Experience with antidiuretic hormone in excretory urography. J Urol 84:577–581, 1960
  35. Lindqvist B: Vasopressin as an aid in locating the kidney in roentgen television for renal biopsy. Acta Med Scand 181:97–99, 1967
  36. Svenningsen NW, Aronson AS: Postnatal development of renal concentration capacity as estimated by DDAVP-test in normal and asphyxiated neonates. Biol Neonate 25:230–241, 1974

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