Synthesis of new vasotocin analogues: effects on renal water and ion excretion in rats

Abstract

Vasopressin and nonmammalian hormone vasotocin are known to increase the water permeability of mammalian collecting ducts, frog skin and the urinary bladder. Neurohypophysial nonapeptides have also been shown to interfere with the regulation of renal ion transport. The subject of this study was a search for vasopressin and vasotocin analogues with selective effects on renal water, sodium and potassium excretion. During this study, we synthesised the following peptides: 13 vasotocin analogues modified at positions 4 (Thr or Arg), 7 (Gly or Leu) and 8 (D-Arg, Lys or Glu); 4 vasopressin analogues modified at positions 4 and 8; and 9 peptides shortened or extended at the C-terminal or with substitutions for Gly-NH2. Most of these peptides had mercaptopropionic acid (Mpa) instead of Cys in position 1. The effects of these nonapeptides on renal water, sodium and potassium transport were evaluated in in vivo experiments using Wistar rats. Some nonapeptides possessed antidiuretic, natriuretic and kaliuretic activities ([Mpa(1)]-arginine vasotocin, [Mpa(1), homoArg(8)]-vasotocin, [Mpa(1), Thr(4)]-arginine vasotocin and [Mpa(1), Arg(4)]-arginine vasopressin). Substitutions at positions 4 and 8 increased the selectivity of peptide actions. The antidiuretic [D-Arg(8)]-vasotocin analogues had no effects on sodium excretion. [Mpa(1), Arg(4)]-arginine vasotocin was antidiuretic and kaliuretic but not natriuretic. [Mpa(1), Glu(8)]-oxytocin had weak natriuretic activity without any effects on water and potassium transport. In accordance with the data obtained, synthesised vasotocin analogues could be good candidates for pharmaceuticals selectively regulating renal sodium and potassium transport, which is of clinical importance.

The effects of neurohypophysial nonapeptides and their analogs on magnesium excretion in rat kidney

“…Increasing a dose of the administered nonapeptide (dAVT, dTAVT, dTDAVT) from 0.0001 to 0.001 nmol per 100 g of body mass led to the antidiuretic effect enhancement and more pronounced decrease in excretion of magnesium ions. At greater doses (0.025-0.1 nmol per 100 g of body weight) in some vasotocin analogs, retaining and enhancing antidiuretic activity (increased solute-free water reabsorption), saluretic activity arose [12,14], i.e. the ability to intensify the excretion of osmotically active compounds, specifically, cations.…”

“…Vasotocin administration to rats increases the solute-free water reabsorption in the kidneys and excretion of sodium, potassium and magnesium ions [12,13]. A series of vasotocin analogs having different effects on the renal transport of water and cations were synthesized [14][15][16][17].…”