Comparative studies on the central effects of the angiotensin II analogue (Sar1 azaVal3 Ile8) AT II.

The effects of the newly-synthesized AT II analogue (Sar1 azaVal3 Ile8) AT II were investigated in comparison with the octapeptide AT II and the analogue saralazin (Sar1 Ala8) AT II, using intracerebroventricular administration, with respect to the following parameters: the level of biogenic monoamines (DA, NA and 5-HT) and the metabolites HVA and 5-HIAA in mouse forebrain; the behaviour of the animals--cataleptogenic actions of mice, PTZ convulsive--seizure threshold in mice, apomorphine stereotypy in rats and behaviour of rats in a conflict situation. The analogue (Sar1 azaVal3 Ile8) AT II, unlike saralazin and AT II, was found to induce a rise in the NA and 5-HT levels, causing also catalepsy that is different from the catalepsy induced by saralazine, AT II and haloperidol, because of its rapid onset and decline; it increases the PTZ convulsive--seizure threshold and reduces the number of punished responses to the conflict drinking test (anxiomimetic effect) in a dose 20 times lower than the dose inducing the remaining effects. This effect was antagonized by saralazine. It is concluded that the newly-synthesized analogue (Sar1 azaVal3 Ile8) AT II induces effects similar to those caused by AT II, being at the same time different to a certain extent from the effects (quantitative and qualitative) of octapeptide AT II.

Comparative studies on the central effects of angiotensin II and of its fragments.

Comparative studies were carried out of the central effects of the octapeptide angiotensin II (AT II) and of its fragments: C-terminal hexapeptide (AT 3-8), middle tetrapeptide (AT 3-6) and initial tripeptide (AT 1-3). The experiments were carried out with respect to the cerebral level of the biogenic amines DA, NA, 5-HT and their metabolites HVA and 5-HIAA in intact mice and in mice pretreated with haloperidol, as well as with respect to the animals' behaviour (haloperidol catalepsy, apomorphine stereotypy, unconditioned jumping reaction, hexobarbital sleep and the threshold of convulsive seizures induced by times intravenous infusion of pentylenetetrazol). The fragments studied were found to manifest activity in the tests used. In some respects this activity is very similar to the activity of AT II. There are also effects which differ from those of AT II, as well as effects which are entirely opposite in some respects, which makes it possible to examine some of these substance as its potential natural antagonists. All this shows that the biological activity of AT II in the brain undergoes a number of qualitative and quantitative changes when its molecule broken to produce peptides with shorter chains. In the effects observed AT II and its fragments interact predominantly with the DA-ergic transmission in the brain.

Central effects of angiotensin II, its fragment and analogues.

The effects of the octapeptide angiotensin II (AT II), its fragment Ile8 AT3-8 and the analogues Sar1 Ala8 AT II, Ala8 AT II and Ile8 AT II were studied with respect to: the level of biogenic amines (DA, 5-HT and their metabolites HVA and 5-HIAA) in the forebrain; the behaviour of the animals--haloperidol catalepsy, apomorphine stereotypy, unconditioned jumping reaction (UJR), convulsive threshold. Good correlation was found between the biochemical and behavioural effects. The fragment of AT II where phenylalanine is substituted at the C-terminal by Ile reduces the haloperidol-increased content of HVA, potentiates apomorphine stereotypy and reduces catalepsy, whereas the AT II analogues (where the C-terminal phenylalanine is substituted by Ala, and the N-terminal--by Sar) potentiate the effect of haloperidol increasing the HVA content, reduce apomorphine stereotypy and potentiate catalepsy; saralasine independently applied induces brief catalepsy; AT II, its fragment and analogues inhibit UJR, in combination with amphetamine and PTZ this effect becomes deeper; the duration of hexobarbital sleep is increased. The peptides investigated increase the convulsive threshold. The results show that the hexapeptide fragment has preserved the effects of AT II, whereas in the analogues (with changed C- and N-terminals) they are changed. The results obtained may be explained with the modulating influence of AT II-receptors on the DA-ergic receptors in the brain structures with which AT II and its fragment and analogues enter in contact.