Intracerebroventricular infusion of angiotensin AT2 receptor agonist novokinin aggravates some diabetes-mellitus-induced alterations in Wistar rats.

Cumulative data suggest the significant role of the renin-angiotensin system in the development of the pathological consequences of diabetes mellitus (DM). Newly synthesized AT2 receptor agonists gained importance as a target for creating new antihypertensives. The aim of the present work was to study the effects of peptide AT2 agonist novokinin, infused intracerebroventricularly, on the consequences of the streptozotocin-induced type 1 DM (T1DM) in Wistar rats. Food and water consumption, body mass, urine excretion (metabolic cages), motor activity (open-field test), anxiety (elevated plus maze), nociception (paw pressure analgesimeter test), spatial memory (T-maze alternation test), and plasma levels of glucose and corticosterone (ELISA) were assessed 2 weeks after the T1DM induction. Novokinin increased water and food consumption, as well as urine output, and reduced mass gain in the control rats. Diabetic rats demonstrated hyperalgesia, increased level of plasma corticosterone, decreased motor and exploratory activity, and impaired spatial memory. Novokinin infusion increased water intake, diuresis, and mortality rate, decreased food intake, exacerbated diabetes-induced hyperalgesia, and provoked anxiety-like behavior but improved spatial memory in diabetic rats. These initial data suggest that angiotensin AT2 receptors participate in the pathogenesis of T1DM-induced complications in the function of the nervous system.

Effect of endurance training on seizure susceptibility, behavioral changes and neuronal damage after kainate-induced status epilepticus in spontaneously hypertensive rats.

The therapeutic efficacy of regular physical exercises in an animal model of epilepsy and depression comorbidity has been confirmed previously. In the present study, we examined the effects of endurance training on susceptibility to kainate (KA)-induced status epilepticus (SE), behavioral changes and neuronal damage in spontaneously hypertensive rats (SHRs). Male SHRs were randomly divided into two groups. One group was exercised on a treadmill with submaximal loading for four weeks and the other group was sedentary. Immediately after the training period, SE was evoked in half of the sedentary and trained rats by KA, while the other half of the two groups received saline. Basal systolic (SP), diastolic (DP) and mean arterial pressure (MAP) of all rats were measured at the beginning and at the end of the training period. Anxiety, memory and depression-like behaviour were evaluated a month after SE. The release of 5-HT in the hippocampus was measured using a liquid scintillation method and neuronal damage was analyzed by hematoxylin and eosin staining. SP and MAP of exercised SHRs decreased in comparison with the initial values. The increased resistance of SHRs to KA-induced SE was accompanied by an elongated latent seizure-free period, improved object recognition memory and antidepressant effect after the training program. While the anticonvulsant and positive behavioral effects of endurance training were accompanied by an increase of 5-HT release in the hippocampus, it did not exert neuroprotective activity. Our results indicate that prior exercise is an effective means to attenuate KA-induced seizures and comorbid behavioral changes in a model of hypertension and epilepsy suggesting a potential influence of hippocampal 5-HT on a comorbid depression. However, this beneficial impact does not prevent the development of epilepsy and concomitant brain damage.

Transient changes of cortical interhemispheric responses after repeated caffeine administration in immature rats.

Repeated postnatal caffeine treatment of rat pups led to transient developmental changes in cortical epileptic afterdischarges. To know if physiological cortical functions are also affected transcallosal evoked potentials were studied. Rat pups of the Wistar strain were injected daily with caffeine (10 or 20 mg/kg s.c.) from postnatal day (P) 7 to P11, control siblings received saline. Cortical interhemispheric responses were tested at P12, 18, 25 and in young adult rats. Amplitude of initial monosynaptic components was evaluated in averaged responses. Single pulses as well as paired and frequency (five pulses) stimulations were used. Developmental rules - highest amplitude of responses in 25-day-old rats, potentiation with paired and frequency stimulation present since P18 - were confirmed. Caffeine-treated rats exhibited transient changes: single responses were augmented in P25 if high stimulation intensity was used, paired-pulse and frequency responses were higher in experimental than in control animals at P12, the opposite change was observed in 18- and more markedly in 25-day-old rats. No significant changes were found in adult animals, monosynaptic transcallosal responses represent a simple and robust system. The developmental profile of described changes did not exactly correspond to changes in epileptic afterdischarges supporting the possibility that afterdischarges did not arise from early monosynaptic components of responses. In spite of transient nature of changes they can reflect delayed or more probably modified brain development.

Dose-dependent effects of caffeine on behavior and thermoregulation in a chronic unpredictable stress model of depression in rats.

The effects of the non-selective adenosine A(1)/A(2) receptor antagonist caffeine on behavior and thermoregulation in chronic unpredictable stress (CUS) model of depression was studied in Wistar rats. In the open field (OF) test, caffeine dose-dependently increased motor activity while decreased grooming and time spent in the corner. Five-week exposure to CUS procedure had the opposite effect in rats. Caffeine reversed CUS-induced effects on the above mentioned parameters. Caffeine (40 mg/kg) increased the motor activity in plus maze (PM) test while at doses of 20 and 40 mg/kg it decreased the number of entries in the open arms. Whereas CUS did not change the level of anxiety, caffeine (2, 20 and 40 mg/kg) administered after CUS diminished it by increasing the time in open arms. Caffeine dose-dependently decreased the immobility time while CUS had the opposite increasing effect in forced swimming test (FST). Caffeine at doses of 20 and 40 mg/kg reversed the effect of CUS on immobility in FST. Caffeine produced dose-dependent rice of body temperature in both non-treated and CUS-treated rats. The hyperthermic effect in normal rats pretreated with caffeine lasted about 90 min while in caffeine-pretreated rats exposed to CUS it lasted about 150 min. High dose of caffeine (100mg/kg) induced significant hypothermia between 90th and 150th minute in control rats and hyperthermia between 30th and 60th minute in CUS-treated rats. These results suggest a putative role of this methylxanthine in the adaptive responses to chronic unpredictable stress stimuli.

The effects of sarmesin, an Angiotensin II analogue on seizure susceptibility, memory retention and nociception.

The present research studies the effects of sarmesin [Sar(1)Tyr(OMe)(4)] Angiotensin II (ANG II), an analogue of ANG II, on the seizure susceptibility, memory activity and nociception. It was found that this octapeptide, administered i.c.v., dose-dependently decreased the seizure intensity (pentylenetetrazol (PTZ) generalized seizure model and PTZ kindling) and augmented PTZ seizure threshold in mice. Sarmesin impaired the memory upon re-testing of rats 24 h later in the passive avoidance test. It decreased the pain threshold in a paw pressure nociceptive assay in rats. ANG II exerted pronociceptive effect as well. Taken together, these results reveal sarmesin as a behaviorally active peptide in the studied experimental animal models.

Interaction of angiotensin II and III with adenosine A(1) receptor-related drugs in passive avoidance conditioning in rats.

The present study examines the functional interaction between angiotensins (ANG II and III) and adenosine A(1) receptor-related drugs on passive avoidance (step-through) conditioning in rats. ANG II and III were administered intracerebroventricularly (i.c.v.) while N(6)-cyclohexyladenosine (CHA) and theophylline-intraperitoneally (i.p.), immediately after the training trial. ANG II (0.1,0.5,1 microg) induced dose-dependent (inverted-U) increase of the retention while ANG III in the same doses decreased it upon re-testing of rats 24 h and 7 days later. The selective adenosine A(1) receptor agonist CHA (0.1 mg/kg) attenuated memory-enhancing effect of ANG II (0.1 microg) 24 h but not 7 days after the training session. Conversely, CHA had opposite i.e. facilitating effect on ANG III (0.1 microg) response upon re-testing 24 h and 7 days later. The pretreatment with ANG III attenuated the retention-improving effect exerted by the non-specific adenosine A(1)/A(2) receptor antagonist theophylline (75 mg/kg) 24 h and 7 days after the training trial. Taken together, the results show a mutual interaction of the drugs belonging to the adenosine and angiotensin modulatory systems in memory consolidation of rats.

Effects of angiotensin III and angiotensin IV on pentylenetetrazol seizure susceptibility (threshold and kindling): interaction with adenosine A(1) receptors.

The effects of angiotensin (ANG) III and ANG IV on pentylenetetrazol (PTZ) seizure susceptibility--threshold and kindling in mice--as well as the influence of adenosine A(1) receptor agents (agonist and antagonist) on these effects were studied. It was found that ANG III and ANG IV increased dose-dependently the PTZ seizure threshold and decreased the seizure intensity in PTZ kindled mice. Cyclohexyladenosine (CHA), an adenosine A(1) receptor agonist, potentiated the effects of ANG III and ANG IV on the seizure threshold and kindling, whereas DPCPX (an A(1) receptor antagonist) reversed peptide-induced effects on the PTZ kindling. Taken together, ANG III and ANG IV decrease the PTZ seizure susceptibility. We could suggest that these effects are realized in part through interaction with adenosine A(1) receptors.

Interaction between angiotensin IV and adenosine A(1) receptor related drugs in passive avoidance conditioning in rats.

The functional interaction between ANG (3--8) (ANG IV) and adenosine A(1) receptor related drugs in passive avoidance (step-through) task in rats was studied in Wistar rats. ANG IV exerted dose-dependent (inverted-U) improvement of the retention while sarilesin (an angiotensin II analog) impaired this effect. Co-administration of theophylline and ANG IV, both in ineffective doses, enhanced the retention. The selective adenosine A(1) receptor agonist cyclopentyladenosine (CPA) attenuated ANG IV-induced memory enhancement.

Long-term theophylline treatment changes the effects of angiotensin II and adenosinergic agents on the seizure threshold.

The effects of angiotensin II (ANG II), sarmesin, losartan, PD 123319, and adenosine A (1) receptor agonist N(6)-cyclopentyladenosine (CPA) administered i.c.v. in untreated and in theophylline-treated male mice (50 mg/kg i.p. twice daily for 14 days) were studied on the pentylenetetrazol (PTZ) seizure threshold. The threshold was increased after long-term theophylline treatment. ANG II, sarmesin, and CPA increased the threshold in theophylline-untreated mice, whereas it decreased the threshold in theophylline-treated animals. Losartan did not change the threshold in theophylline-untreated mice but decreased it in theophylline-treated animals. PD 123319 did not change the seizure threshold both in theophylline-untreated and -treated mice. Taken together, the data demonstrated that repeated exposure to theophylline selectively changes the effects of ANG II and adenosinergic agents on the PTZ seizure threshold. The results indicate that both angiotensin AT(1) and adenosine A(1) receptor subtypes could possess interactive mechanisms of adaptation to chronic theophylline treatment.

Adenosine-angiotensin II interactions in pentylenetetrazol seizure threshold in mice.

The effects of adenosinergic and angiotensin IIergic agents and of their combinations on the seizure threshold in mice were determined by measuring the dose of timed-intravenous (tail vein) infused pentylenetetrazol (PTZ) required to elicit clonic seizures. All drugs were administered intracerebroventricularly (i.c.v.). Angiotensin II (ANG II), its peptide analogue sarmesin, the selective adenosine A1 receptor agonists N6-cyclopentyladenosine (CPA) and 2-chloroadenosine (2-ClAdo) significantly increased the PTZ seizure threshold. The selective AT1 receptor antagonist losartan blocked the anticonvulsant effect of ANG II, sarmesin and CPA. The selective AT2 receptor antagonist PD 123319 failed to block the effect of ANG II and sarmesin on the PTZ seizure threshold but reversed the threshold-increasing effect of CPA. The selective adenosine A1 receptor antagonist 8-(p-sulfophenyl)-theophylline (8-p-SPT) alleviated the threshold-increasing effect of CPA and ANG II. Concurrent injection of 2-ClAdo and ANG II as well as of 2-ClAdo and sarmesin, at doses which had no significant effect on the PTZ seizure threshold when given alone, acted synergistically, producing greater effect on the threshold. Taken together, the findings support the possibility of specific ANG II-adenosine A1 receptor interactions in the regulation of the PTZ seizure threshold.

Further evidence for interaction between angiotensin II and dopamine receptors (experiments on apomorphine stereotypy).

The present study was undertaken to further evaluate the effects of angiotensinergic agents: angiotensin II (AII), its analogues sarmesin ([Sar1, Tyr(Me)4]AII) and sarilesin ([Sar1, Ile8]AII), as well as DuP 753, a nonpeptide selective AT1 receptor antagonist, on apomorphine stereotypy in rats thus providing further evidence for AII-DAergic receptor interactions. All drugs were administered intracerebroventricularly (i.c.v.). Stereotyped behavior was evoked by an i.p. injection of 3 mg/kg apomorphine. AII (0.1-5 micrograms) exerted a decrease on stereotypies (U-shaped); the effect being significant at doses of 1 and 2 micrograms. Sarmesin significantly increased apomorphine stereotypy at a dose of 5 micrograms and decreased it at a dose of 20 micrograms. Sarmesin (10 micrograms) reversed the decreasing effect of AII (2 micrograms) leading to a more pronounced increase of stereotypies. Sarilesin (5 micrograms), which by itself is inactive, also demonstrated antagonistic properties when injected 5 min before AII (2 micrograms). DuP 753 (100 micrograms) alone had no significant effect on apomorphine stereotypy, but injected 5 min before AII (2 micrograms) it reversed the decreasing effect of AII on stereotypy. Taken together, the results further confirm the hypothesis that AII closely interacts with DAergic neurotransmission, an effect which is mediated predominantly by AT1 receptors.

Interaction of angiotensin II and adenosine receptors in pentylenetetrazol-induced kindling in mice.

The relationships of adenosine A1 receptor agonists and antagonists in combination with angiotensin II (AT II) and its analogue sarmesin in PTZ (pentylenetetrazol) kindling in ICR mice were studied. The occurrence of clonic and tonic seizures and the latency to their onset in PTZ kindled mice was determined. Combination of adenosinergic and AT II-ergic agents significantly reduced the incidence of clonic seizures in PTZ kindling without changing the latency. Pretreatment with 8-p-Sulfophenyl-theophylline (8-p-SPT) reversed the anti-convulsant effect of sarmesin.