Effects of [arginine8, glycine-OH9]-vasopressin on pentylenetetrazol seizures in mice. Interaction with adrenaline.

The effects of [arginine8, glycine-OH9]-vasopressin (AGV), alone and in combination with adrenaline, on pentylenetetrazol (PTZ) seizure threshold by timed intravenous infusion in tall vein and intensity by subcutaneous (s.c.) PTZ test (85 mg/kg) were studied in male albino mice. AGV was administered intracerebroventricularly (i.c.v.) at doses of 0.001, 0.01, 0.1, 1.0 and 5.0 ng/mouse 5, 15 and 30 min prior to PTZ AGV induced decrease of seizure threshold at middle doses (0.01 and 0.1) 5 and 15 min prior to PTZ (75 and 67% respectively vs. controls). Adrenaline (1 mg/kg, i.p.) potentiated the effect of AGV on seizure threshold. AGV also induced increase of seizure intensity at doses of 0.01 and 1.0 ng and decrease of latency of the first tonic seizure. Adrenaline (1.0 mg/kg, i.p.) enhanced the effects of AGV suggesting interactions of vasopressin with adrenergic neurotransmission in the CNS.

Effects of non-peptide angiotensin II-receptor antagonists on pentylenetetrazol kindling in mice.

The effects of non-peptide AT1- and AT2-receptor antagonists DuP 753 (losartan) and PD 123319 on the intensity of pentylenetetrazol (PTZ)-kindled seizures in mice were studied. PTZ was injected intraperitoneally at a subconvulsive dose of 40 mg/kg at 48 h until the appearance of clonic seizures. DuP 753 administered intracerebroventricularly (i.c.v.) tended to decrease seizure intensity. Successive administration of ineffective doses of DuP 753 (losartan) and AT2 (angiotensin II) significantly decreased seizure intensity. PD 123319 (i.c.v.) decreased seizure intensity. Combination of ineffective doses of PD 123319 and AT2 also significantly decreased seizure intensity. The results suggest the role of AT2 receptor and its subtypes in PTZ-kindled seizures as well as an action of DuP 753 and PD 123319 similar to the action of AT2, an AT2-receptor agonist.

Further evidence for the interactions between angiotensin II and GABAergic transmission in pentylenetetrazol kindling seizures in mice.

The effects of the GABAergic drugs nipecotic acid, Gabrene, baclofen and metatolylcarbamide (MTC), when given alone or in combination at subthreshold doses with AT II also at a subthreshold dose effective on PTZ-kindling in mice were studied. PTZ-kindling was provoked by intraperitoneal (i.p.) injections of PTZ (40 mg/kg) every other day in male albino mice until clonic seizures appeared. Nipecotic acid (100 and 200 micrograms/mouse intracerebroventricularly [i.c.v.]) tended to decrease seizure intensity. Gabrene (25, 50, 100 and 250 mg/kg i.p.) inhibited PTZ-kindled seizures. Baclofen at a doses of 2.5 and 5 mg/kg i.p. tended to decrease seizure intensity and at a dose of 10 mg/kg was ineffective at all. MTC (50 and 75 mg/kg i.p.) tended to decrease and at a dose of 100 mg/kg significantly decreased seizure intensity. Combinations of subthreshold dose of AT II (0.05 micrograms/mouse i.c.v.) and subthreshold doses of nipecotic acid (100 micrograms/mouse) or Gabrene (10 mg/kg) or baclofen (10 mg/kg) or MTC (50 mg/kg) significantly decreased the intensity of PTZ-kindled seizures in mice. The observed potentiation of the anticonvulsive activity on PTZ-kindling suggests interactions of AT II receptors with GABA receptors (GABAA, GABAB or both), effected through allosteric mechanisms.

Interactions between angiotensin II, diazepam, clonazepam and di-n-propylacetate in pentylenetetrazol kindling seizures in mice.

The effects of AT II alone and in combinations with the anticonvulsants diazepam, clonazepam and di-n-propylacetate (depakine) on PTZ-kindling in mice were studied. PTZ-kindling was provoked by intraperitoneal (i.p.) injections of PTZ (40 mg/kg) every other day in male albino mice until clonic seizures appeared. AT II in doses 0.1 and 1 microgram/mouse intracerebronventricularly (i.c.v.) decreased the intensity of seizures in PTZ-kindled mice. Diazepam (0.25 and 1 mg/kg i.p.), clonazepam (0.05 and 0.1 mg/kg i.p.) and depakine (75 mg/kg) inhibited PTZ-kindled seizures. Combinations of ineffective doses of AT II (0.05 microgram/mouse) and ineffective doses of diazepam (0.1 mg/kg) or clonazepam (0.01 mg/kg) or depakine (50 mg/kg) significantly decreased the intensity of seizures in PTZ-kindled mice. The seizure-decreasing effect of diazepam, clonazepam and depakine on PTZ-kindling in mice, which was potentiated by AT II, suggests interactions of AT II receptors with GABA and benzodiazepine receptors or with the GABA-benzodiazepine receptor-ionophore complex, probably effectuated through alsoteric mechanisms. A more efficient coupling of the GABA-benzodiazepine receptor-ionophore complex with AT II receptors might also be the reason for the decrease of the intensity of seizures in PTZ-kindled mice.

Interactions between angiotensin II and baclofen in shuttle-box and passive avoidance performance.

In experiments on male rats, we established that angiotensin-II (AT II) at a dose of 0.1 micrograms injected intracerebroventricularly immediately after training improved memory when retention tests (active and passive avoidance) were given 24 hours later. Baclofen at doses of 2, 5 and 10 mg/kg injected intraperitoneally immediately after training also improved retention in both active and passive avoidance tasks. Baclofen at a dose of 20 mg/kg was without effect on active avoidance performance. Combination of AT II and baclofen (2, 5 and 10 mg/kg) facilitated memory in active avoidance as compared to controls, but impaired retention as compared to the AT II-treated group. The impairment of the AT II-improved retention was stronger when the dose of baclofen in the combination was 20 ng/kg. Combination of AT II and baclofen (10 mg/kg) did not impair retention in passive avoidance. These data favor the view that GABA receptors may interfere with the AT II effects on memory consolidation or retention and that interactions of GABA (GABAA and GABAB) receptors with AT II receptors are of importance for memory processes.

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.

Interactions between angiotensin II, GABA and diazepam in convulsive seizures.

In experiments on male mice, we studied the effects of gamma-aminobutyric acid (GABA), angiotensin II (AT II), administered intracerebroventricularly, diazepam, injected intraperitoneally, and combinations of GABA + AT II and diazepam + AT II on convulsive seizures induced by pentylenetetrazol (PTZ) (80 mg/kg subcutaneously) and 3-mercaptopropionic acid (3-MPA) (40 mg/kg intraperitoneally). The anticonvulsant effects of GABA and diazepam on PTZ-induced seizures were increased by AT II in doses which did not significantly influence seizures. AT II applied together with GABA or diazepam in ineffective doses provoked a strong anticonvulsant effect on both PTZ- and 3-MPA-induced seizures. These results indicate that the anticonvulsant effects of GABA and diazepam on PTZ- and 3-MPA-induced seizures might effectively be potentiated by the octapeptide AT II. It is suggested that AT II operates as an endocoid acting on GABA, respectively benzodiazepine recognition sites in the CNS.

Interactions of angiotensin II and GABA-ergic agents at the threshold of convulsive reactions.

The effects of angiotensin II (AT II), GABA, muscimol (administered i.c.v.) and of amino-oxiacetic acid (AOAA) and baclofen (administered i.p.), as well as of the combinations of AT II with these substances and bicuculline, were studied with respect to the threshold of the convulsive seizures induced by timed intravenous infusion of pentylenetetrazol (PTZ) in mice. It was found in the experiments that the threshold-increasing effect of GABA, muscimol and AOAA was potentiated by AT II (applied in a dose which did not change essentially the convulsive threshold). The potentiated effect of GABA, muscimol and AOAA on the convulsive threshold, when applied in combination with AT II, was antagonized by bicuculline. The threshold-increasing effect of baclofen was not affected substantially by AT II; in this case bicuculline had no effect. On the basis of the results obtained it may be assumed that AT II performs the functions of an antocoid predominantly for the GABA-A receptors in the central nervous system.