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The substitution of glutamine by threonine in position 4 of oxytocin, deamino-oxytocin, deamino-1-carba-oxytocin, and deamino-6-carba-oxytocin was found to increase the elimination rate of all analogs examined from the uterine receptor compartment in rat. However, this substitution was without any effect on the time course of uterotonic response in the case of vasotocin and deamino-vasotocin. These results suggest that the topological relationships of the 4 and 8 positions may show an important effect on elimination rate of oxytocin and vasotocin analogs from the rat uterine compartment.

Protracted effect of [2-0-methyltyrosine]-deamino-1-carba-oxytocin, [2-0-methyltyrosine]-oxytocin and its dimeric form was studied on the mammary gland of lactating rat in vivo. Biphasic course of biological response found for monomers and slow onset of response observed for dimer led to the assumption that the substances behaved like hormonogens.

In conscious dog deamino-dicarba-oxytocin strongly stimulated a spike activity in the uterus which was more prolonged than that after oxytocin. Both oxytocin and deamino-dicarba-oxytocin inhibited the tone and peristaltic contractions of stomach and small intestines in starving dogs, eliminated the spike discharges, reduced the basic electrical rhythm frequency of the stomach and accelerated the propagation velocity of the slow waves in the small intestine. Only oxytocin, but not its deamino-analogue, reduced the pulse frequency and inhibited the spontaneous contractions of muscle strips isolated from the guinea pig stomach and portal vein.

After intracarotid injection of 125I-arginine vasopressin (AVP), 125I- or 3H-lysine vasopressin (LVP), 3H-DesGlyNH2-arginine vasopressin (DGAVP), and 125I- or 3H-oxytocin (OXT), the accumulation of radioactivity was determined in 13 to 18 brain regions and anterior pituitary in rats. Calculated extraction by tight capillary regions amounts to about 1-2% independently of the peptide doses injected (4 X 10(-4) to 5 X 10(-9) mol-1). This indicates a low but measurable extraction of labelled peptides which furthermore is nonsaturable. Among brain regions with tight capillaries, the extraction does not vary obviously. Blood-brain barrier (BBB)-free regions extract up to 30 fold more peptide than BBB-protected regions and the extraction varies considerably between individual regions. Within BBB-free regions, the peptides passed the leaky capillary endothelium, but there is no evidence for a penetration to deeper layers of the brain. It is concluded that endogenous blood-borne peptides cannot pass brain barriers in physiologically significant amounts. This does not exclude a possibility that passive transport of minute but effective amounts might occur if high pharmacological amounts of peptides are injected peripherally. But, as shown, none of the peptides studied possesses properties that favour its passage across the BBB.

The milk-ejecting activity of oxytocin analogues modified in the aminoterminal part of the molecule was determined in experiment on rats in vivo. As compared with oxytocin, the analogues did not have significantly higher milk-ejecting activity and there was no dissociation of the two basic oxytocin-like activities.

Tritiated vasopressin analogue, [8-L-arginine, 9-desglycineamide]-vasopressin was prepared from its diiodo-derivative by means of catalytic reductive dehalogenation. The reaction products were purified by reversed-phase HPLC resulting in a labelled peptide with high specific radioactivity (629 TBq/mmol).

The relation between the duration of antidiuresis and sodium excretion and the route of administration of [8-lysine-vasopressin or [8-D-arginine]-deaminovasopressin to conscious rats was investigated. Both compounds were administered either intravenously through a chronically inserted catheter in the right jugular vein, or subcutaneously. The rats were then placed into individual metabolic cages and urine was collected quantitatively. Subcutaneous administration of both compounds resulted in a more prolonged antidiuretic response, lower sodium excretion and higher total urine osmolality. In order to achieve a comparable half-time antidiuresis, it was necessary to apply about 1000 times higher does of [8-lysine]vasopressin than those of [8D-arginine]deaminovasopressin. The relation between the duration of both antidiuresis and sodium excretion and the way of administration was, however, more pronounced in the case of [8-lysine]vasopressin. The excretion of potassium was increased after both compounds, the highest value being found after subcutaneous administration of [8-lysine]vasopressin.

Non-anaesthetized rats were used for studying the relationship between the amount of sodium excreted and structural modifications of oxytocin molecule. Any change performed in position 4 (i.e. the glutamine residue) resulted in a decrease of natriuretic activity as compared to that of oxytocin. The analogues with modifications in the amino-terminal part of the molecule (e.g. substitution of the amino group in position 1 by hydrogen, or of the disulfide bond by a thioether group) resulted in a higher natriuretic effect than oxytocin.

Nacartocin, [2-p-ethylphenylalanine]deamino-6-carba-oxytocin, is almost three times more potent than oxytocin as a natriuretic agent. The natriuretic effect is mainly due to the inhibitory action of the peptide on tubular sodium resorption. Nacartocin decreased the blood pressure of anesthetized rats by the decrease of the total peripheral resistance which was greater than that observed after oxytocin administration. In conscious rats, Nacartocin caused a slight but prolonged increase of blood pressure.

[Leu4, D-Arg8] vasotocin (I) and [Mpr1, Leu4, D-Arg8] vasotocin (II) possess a considerable and very specific antidiuretic effect. In I, the change of configuration in position 8 caused an increase of the magnitude of the antidiuretic effect. In I, the change of configuration in position 8 caused by two orders and a decrease of the magnitude of the pressor effect by one order. I and II are the first vasotocin analogues reported to have a relatively high and specific antidiuretic effect.