A comparison between haemodynamic effects of vasopressin analogues

Some analogues of arginine vasopressin (AVP) reportedly possess hypotensive properties, and two such peptides are Cys¹-Tyr²-Phe³-Val⁴-Asn⁵-Cys⁶-Pro⁷-d-Arg⁸-Gly⁹-NH₂ (VD-AVP) and d(CH₂)₅-Cys¹-d-Tyr(Et)²-Arg³-Val⁴-Asn⁵-Cys⁶-Lys⁷-Lys⁸-ethylenediamine⁹ (TA-LVP). In the present investigation we examined the effects of TA-LVP (0.3, 1.0 and 3.0 g/kg/min), VD-AVP (0.3, 1.0 and 3.0 g/kg/min) and AVP (1.0, 3.0, 10 ng/kg/min) on haemodynamics, blood volume (BV) and plasma troponin levels in anaesthetised rats. Infusion of TA-LVP significantly (P<0.05) reduced blood pressure (–45±3%; n=8; mean ± SEM), mean circulatory filling pressure (P_mcf; –41±3%), and cardiac output (CO; –59±4%). The reduction in CO at a lower dose of TA-LVP was due to reduced venous tone, while at higher doses the reduction was predominantly the result of reduced BV (–35±4%). The large decrease in BV during the infusion of TA-LVP, substantially increased resistance to venous return (50±11%), which was the main contributor in reducing CO. Administration of AVP significantly increased blood pressure (41±4%) and arterial resistance (98±16%) without any impact on P_mcf and BV, while significantly reducing CO (–26±5%). Infusion of VD-AVP did not produce hypotension, but produced a modest but significant reduction in CO (–18±5%) and insignificant but moderate increases in peripheral resistance (30±12%) and resistance to venous return (28±8%). Plasma troponin levels were not affected by any of the peptides. The hypotensive action of TA-LVP was due to a reduction in CO as a result of a reduced pre-load, while the pressor effect of AVP increased after-load sufficiently to impede flow, reducing CO. VD-AVP was devoid of any hypotensive effects, suggesting that V₂-vasopressin receptors are most likely to play a limited role in the control of cardiac and vascular function in these animals.     

Bilateral transections of temporo-entorhinal connections attenuate vasopressin improvement of memory in rats.

It has been found in our laboratory that the positive influence of vasopressin (AVP) on memory processes is mediated by excitatory amino acids, since it was abolished by NMDA receptor antagonists. The purpose of the present study was to investigate whether bilateral transections of glutamatergic temporo-entorhinal connections may have an influence on the facilitatory effect of AVP on retrieval process of a passive avoidance behaviour. The bilateral transections of temporo-entorhinal connections were made in male Wistar rats 10 days before testing of the influence of intracerebroventricular AVP (1 microgram per rat) injection on memory, evaluated in a passive avoidance task. Although AVP significantly facilitated the retrieval process both in sham-operated and in lesioned groups of rats, bilateral disruption of temporo-entorhinal connections significantly attenuated the facilitatory effect of AVP on the retrieval process. Moreover, bilateral transections of temporo-entorhinal connections failed to affect motor activity, such as crossings of squares, without an influence on rearings and bar approaches evaluated in an open field test. These results may suggest that in the facilitatory effect of AVP on the retrieval process is involved a reciprocal glutamatergic connection between the lateral entorhinal cortex and the temporal cortex.     

Cardiovascular effects of angiotensin II and vasopressin in intact awake rats

• 1.1. In this study we evaluated, in intact awake rats, the effects of angiotensin II (AII) and vasopressin (AVP) on venous tone to explain their different hemodynamic effects.
• 2.2. Cardiac index (CI) was measured by thermodilution. AII and AVP were infused at the doses adjusted to increase mean arterial pressure 25, 50 and 70% above baseline. Lower doses of AVP than AII were necessary to increase mean arterial pressure at the same levels.
• 3.3. To study whether the different effectes of AII and AVP on CI may be explained by their different actions on the venous system, changes in venous tone were evaluated by measuring mean circulatory filling pressure (MCFP) and determining the pressure gradient for venous return (PGVR).
• 4.4. AVP induced a decrease in CI from 32.5 ± 2.2 to 23.1 ± 1.7 and 15.4 ± 0.8 ml/min/100 g (P < 0.01) with the second and third level of increase in afterload respectively, whereas AII at the same levels of afterload decreased CI from 34.8 ± 1.3 to 28.3 ± 2.3 and 23.4 ± 1.7 ml/min/100 g (P < 0.01). Furthermore, the rise in total peripheral resistances (TPR) was greater with AVP than with AII at the highest level of afterload (P < 0.05). Heart rate significantly decreased more in the animals infused with AVP than with AII.
• 5.5. There were no changes in MCFP and PGVR with either AII or AVP.
• 6.6. These results indicate that in intact awake rats the larger fall in CI induced by AVP can not be explained only by a greater decrease in HR since at highest levels of afterload AVP decreased SV. This result may be explained by a greater arteriolar vasoconstrictor effect of AVP than AII for augmenting TPR and decreasing venous return.

     

Time-related effects of benzodiazepines on intestinal motility in conscious dogs

The effects of diazepam and GABA on intestinal motility were investigated in fasted dogs fitted with strain-gauge transducers. Injected intravenously at 9.00 and 16.00 h, diazepam (0.5 mg kg-1) affected intestinal motility only during darkness i.e. from 19.00 to 7.00 h. These jejunal motor effects which were mimicked by GABA, (0.3 mg kg-1 i.v.) corresponded to a disruption of the migrating myoelectric complex (MMC) with an increased contractile activity. These results demonstrate that benzodiazepines affect the intestinal motility in dog and suggest that the effects are related to sleep-stages.     

Hypertonic saline mimics the effects of vasopressin and social recognition in rats

Injection of hypertonic saline to adult male rats following exposure to a juvenile, at a dose known to release peripheral and central vasopressin (10ml/kg i.p. of an 0.5M solution), decreased social exploration of the same juvenile when it was presented 2h later. This effect of hypertonic saline was blocked by pretreatment with subcutaneous injection of 30mg/kg dPTyr (Me) AVP, an antagonist of the vasopressor receptors of vasopressin, in intact but not in castrated male rats. These results are interpreted in terms of the involvement of androgen-dependent vasopressinergic neurotransmission in social recognition.     

Cardiovascular effects of neurotensin and some analogues on rats

When administered in vivo into the femoral vein of normotensive rats, neurotensin, neurotensin-(8-13), and [D-Lys8]neurotensin-(8-13) decreased diastolic blood pressure in a dose-dependent manner, without change in heart rate. All three peptides evoked tachyphylaxis and a triphasic depressor-pressor-depressor, response at higher doses. The rank order of potency was neurotensin greater than [D-Lys8]neurotensin-(8-13) greater than neurotensin-(8-13). In organ chamber experiments, both neurotensin and neurotensin-(8-13) at a range of concentrations which induced dose-dependent decreases in blood pressure, did not significantly change tension in rat aorta rings with or without endothelium. In contrast, [D-Lys8]neurotensin-(8-13) induced weak dose-dependent relaxation of both rings with or without endothelium. However, this effect was not obtained at concentrations able to decrease the blood pressure. Indomethacin did not change the vasodilator effect of [D-Lys8]neurotensin-(8-13). There was no correlation between the vasodilator effect of this peptide and its ability to decrease blood pressure. These experiments suggest that the hypotension was not due to a direct vasodilator effect on the smooth muscle. In addition, since the rank order of peptide potency was opposite of those found in previous studies of second messenger synthesis and binding to neural tissue, these data suggest that there is a second receptor for neurotensin or that neurotensin can also bind to a different unknown receptor.     

Behavioral and memory improving effects of mirtazapine in rats

These experiments examined the effects of the antidepressant mirtazapine in several behavioral and memory tests. The tests were carried out on male Wistar rats weighing about 200 g. The drugs were injected 30 min before the tests. The aim of the locomotor activity test was to select a dose which had no influence on the motility of the animals and, at the same time, was active at least in one behavioral test. The chosen dose was 2.5 mg/kg. In the two-compartment exploratory test, 2.5 mg/kg of mirtazapine had a distinct anxiolytic effect after the first treatment, after 7 days the effect was weaker but still significant and it disappeared after 14 days. In the forced swimming test, the immobility time was shortened only after 14 days of administering the drug. In the maze test, mirtazapine shortened the food finding time (it improved memory) and counteracted memory loss induced by scopolamine. In the conditioned avoidance responses test (CARs), mirtazapine improved memory only after its earlier impairment by scopolamine. The authors cohclude, contrary to some published data, that after proper dose (adequate for other tests but not for the locomotor activity test), mirtazapine has a distinct memory improving activity or a memory restoring effect after scopolamine treatment.     

Neuromodulation of memory in the hippocampus by vasopressin

The involvement of [Arg(8)]vasopressin in memory processes was analyzed in the hippocampal structure, since we have reported that this is one of the main central target structures of the vasopressin-enhancing effect on memory. This structure is functionally differentiated along its dorsoventral axis, and the expression of the vasopressinergic system is dependent upon whether the dorsal or ventral part of the hippocampus is involved. For this reason, the effect of vasopressin injected into hippocampus was evaluated on the basis of the site of injection. We have shown, using a Go-No Go visual discrimination task with mice that both parts of the hippocampus are involved in the effect of endogenous or exogenous vasopressin, but with higher sensitivity for the ventral part. Based on the expression of Fos protein following intracerebroventricular injection of vasopressin in unconditioned or conditioned mice, we confirmed the greater involvement of the ventral hippocampus in the enhancing effect of vasopressin on memory processes. The effect of the peptide seems specific, since only a few of the hippocampal cells that expressed Fos protein in the unconditioned mice did so in the conditioned mice (cells in the dentate gyrus and the CA3 hippocampal field). Moreover, we have shown that in the ventral hippocampus, vasopressin generates different behavioral effects whether treatment is performed at the beginning or in the middle of the learning process, suggesting that the mnemonic context is an important factor for understanding the effect of vasopressin on memory in the ventral hippocampus.     

外源性神经节苷脂对铅暴露大鼠学习记忆及海马精氨酸加压素的影响

目的:研究外源性神经节苷脂-1(GM_1)对铅暴露大鼠学习记忆能力及海马细胞精氨酸加压素(AVP)的影响。方法:健康2月龄SD大鼠60只随机分为正常对照组、模型组和GM_1组。正常对照组饮用去离子水,其余2组饮用0.1%醋酸铅去离子水制成慢性染铅大鼠模型。3 mo后,GM_1组腹腔注射GM_1 50 mg·kg~(-1),正常对照组和模型组腹腔注射等量生理盐水,均为14 d。以Y-迷宫试验检测各组大鼠的学习和记忆能力,采用免疫组化的方法测定大鼠海马AVP,并观察其阳性神经元数量的变化。结果:模型组大鼠学习记忆能力较正常对照组明显减低,海马CA_1区AVP阳性神经元数量减少,有统计学意义(P<0.01);GM_1组腹腔注射GM_1后,Y-迷宫错误次数减少,且有统计学意义(P<0.05),其海马CA_1区AVP阳性神经元数量增多,且有统计学意义(P<0.01),CA_3区AVP阳性神经元数量亦增多且有统计学意义(P<0.01)。结论:外源性GM_1可一定程度的改善染铅大鼠的学习记忆能力,可能与海马细胞AVP的阳性表达增强有关。     

Iodination of vasopressin analogues with agonistic and antagonistic properties: effects on biological properties and affinity for vascular and renal vasopressin receptors

Twelve L- and D-tyrosine-containing vasopressin analogues were prepared in their mono- and diiodinated forms. These include six arginine vasopressin (AVP) vascular (V1) type antagonists/antidiuretic (V2) agonists, four V1/V2 antagonists, and two V1/V2 agonists, one of which is AVP itself. Ten peptides were iodinated on the tyrosyl residue in position 2; two were iodinated on a tyrosyl amide residue replacing the glycyl amide residue at position 9. All peptides were tested both for their biological activities in vivo (rat vasopressor and antidiuretic tests) and for their ability to bind to vasopressin receptors of the V1 (vascular) and V2 (renal) types from rat liver and rat kidney membranes, respectively. It is shown that monoiodination of the tyrosyl residue in the vasopressin analogues that were tested either preserves or reduces to a highly variable extent the in vivo and in vitro biological activities of these analogues. In most cases diiodonitation resulted in a marked decrease in biological activity. The effects of iodination on the affinity of vasopressin analogues for hepatic V1 receptors and renal V2 receptors were more related to the affinity of the noniodinated peptide for these receptors than to the biological properties (antagonist versus agonist) of the tested analogues, the nature (L versus D) of the iodinated tyrosyl residue, or the position (2 versus 9) at which this residue was introduced. The loss of affinity due to iodination was usually more pronounced for peptides exhibiting high affinity for vasopressin receptors. However, we show that among the monoiodinated peptides some (especially monoiodinated [2-D-Tyrosine]-AVP) retained enough affinity for vasopressin binding sites to suggest that their radioiodinated conterparts would be promising labeled ligands for use in studies in vasopressin receptors.     

Antiamnesic effects of D-pipecolic acid and analogues of Pro-Leu-Gly-NH2 in rats

The antiamnesic effects of prolyl-leucyl-glycinamide (PLG) and analogues of this tripeptide were investigated in rats. Retrograde amnesia was induced by electroconvulsive shock treatment and the degree of amnesia was characterized by the attenuation of one-trial learning passive avoidance response. PLG resulted in dose-dependent attenuation of retrograde amnesia. Structural modifications included N-terminal protection, substitution of the C-terminal NH2 group, replacement of the N-terminal amino acid, and replacement of the second amino acid of the tripeptide. Some tripeptides, all of them containing D-pipecolic acid instead of the N-terminal proline, were more effective than PLG. Therefore, D-pipecolic acid, D-pipecolamide and their N-terminally protected analogues were also investigated, and were found to have powerful antiamnesic effects.     

Spatial working memory in rats: effects of monoaminergic antagonists

To assess the possible involvement of the monoaminergic neurotransmitters norepinephrine, dopamine and serotonin in the maintenance of spatial working memory rats were treated with antagonists 0 or 2 hr after completing the first 4 choices in an 8 arm maze. Haloperidol (0.25-1 mg/kg), when administered 2 hr after Choice 4, produced a small but consistent impairment in performance on retention tests given 5 hr after the first 4 choices. This deficit closely resembled natural forgetting in terms of the type of errors committed. By contrast, haloperidol in the same doses given 0 hr after Choice 4 or 3 hr before the first 4 choices did not affect retention. Likewise treatment with propranolol (10-20 mg/kg), phentolamine (5-20 mg/kg) or methysergide (5-15 mg/kg) did not impair spatial memory, regardless of when these drugs were injected within the session. Evidently dopaminergic neuronal systems are important in the maintenance of normal spatial working memory.     

Effects of vasopressin on histamine H(1) receptor antagonist-induced spatial memory deficits in rats.

The effects of [Arg(8)] vasopressin on histamine H(1) receptor antagonist-induced memory deficits were investigated using the eight-arm radial maze performance test in rats. Pyrilamine and diphenhydramine as well as scopolamine induced memory deficits characterized by increases in the number of total errors, reference memory errors and working memory errors. [Arg(8)] vasopressin improved not only scopolamine--but also pyrilamine--and diphenhydramine-induced memory deficits, although a high dose of [Arg(8)] vasopressin was needed to antagonize pyrilamine-induced memory deficits. The effects of pyrilamine on the brain [Arg(8)] vasopressin content were studied, and the hippocampus [Arg(8)] vasopressin content was shown to be decreased after pyrilamine injection. From these observations, it seems likely that [Arg(8)] vasopressin participates in not only the cholinergic system but also the histaminergic system in spatial memory.     

Antianginal effects of lercanidipine on the vasopressin or methacholine induced anginal model in rats

The antianginal effects of lercanidipine, a newly synthesized 1,4-dihydropyridine derivative calcium channel antagonist, were evaluated in experimental angina model rats and the effects were compared with those of nifedipine, benidipine and amlodipine. In the vasopressin-induced angina model, intravenous administration of lercanidipine dose-dependently suppressed vasopressin-induced ST-depression. Amlodipine barely suppressed it, while benidipine, at the same dose, completely suppressed it. Nifedipine had a potency between that of amlodipine and benidipine. Oral administration of lercanidipine showed similar effects to the intravenous administration test on ST change. High doses of amlodipine, benidipine and nifedipine suppressed ST-depression by almost 100%. In the methacholine-induced angina model, lercanidipine suppressed the ST elevation dose dependently. Amlodipine barely suppressed it, while benidipine at 30 microg/kg effected almost total suppression. Nifedipine had a potency between that of amlodipine and benidipine. Intraduodenal administration of lercanidipine also suppressed the ST-elevation dose dependently. Nifedipine, benidipine and amlodipine at 10 mg/kg all markedly suppressed the elevation. Lercanidipine was more potent than the other calcium channel antagonists tested. In conclusion, it was explicitly demonstrated that lercanidipine exerts potent protective effects on the ischemic electrocardiography (ECG) changes in a variety of putative angina pectoris models in rats. An antispasmolytic coronary vasodilating action may be involved in the mechanism. It is expected that lercanidipine will be useful as an antianginal agent.     

Baclofen interactions with nicotine in rats: effects on memory

Nicotine has been shown in numerous previous studies to significantly improve memory on the radial-arm maze, yet the critical mechanisms underlying this effect are not fully characterized. Nicotine stimulates the release of a number of neurotransmitters important for memory function including (gamma-aminobutyric acid) GABA. The importance of nicotinic-GABA interactions regarding memory is currently unknown. The purpose of the current study was to determine the interactive effects of nicotine and the GABA agonist baclofen on working memory function as measured by choice accuracy in the radial-arm maze. Female Sprague-Dawley rats trained to asymptotic performance levels on a win-shift eight-arm radial maze task were used for assessment of nicotine-baclofen interactions. Low doses of baclofen improved memory performance while higher doses impaired it. Nicotine, as seen before, improved memory performance. Nicotine also significantly reversed the higher dose baclofen-induced deficit. These data show the importance of both nicotinic and GABA systems in working memory function and the interactions between these two transmitter receptor systems. This not only provides information concerning the neural bases of cognitive performance, it also lends insight into new combination treatments for memory impairment.     

The effects of serotonergic drugs on short-term spatial memory in rats

The effects of modulating the serotonergic system on short-term spatial memory were investigated using delayed matching to position and delayed non-matching to position procedures. Rats were trained on one of the two tasks until stability and then administered the drugs 30 min before a session. Fluoxetine (0.625-10 mg/kg), a serotonin uptake inhibitor, fenfluramine (0.313-5 mg/kg), a serotonin release enhancer, and ipsapirone (2.5-10 mg/kg), a serotonin 1A partial agonist, were all injected subcutaneously in saline solution. Apart from fenfluramine, none of the compounds affected accuracy in either procedure, but some effects on other non- mnemonic measures were seen. At 5 mg/kg, fenfluramine significantly affected latency to respond, total responses on the levers and nosepokes in the foodtray as well as accuracy, indicating a non-specific disruption of behaviour rather than a selective effect on memory processes. These data suggest that cognitive effects of serotonergic drugs are difficult to identify in normal animals, irrespective of the mechanism of action of the drug. These data conflict with recent reports indicating memory-enhancing effects of serotonin uptake inhibitors.     

Cardiovascular effects of injections of vasopressin into the nucleus tractus solitarius in conscious rats.

The effects of injections of arginine vasopressin (AVP) into the nucleus tractus solitarius (NTS) on mean arterial pressure (MAP), heart rate (HR) and plasma concentrations of noradrenaline and adrenaline were investigated in conscious, unrestrained rats. Injection of 2 ng AVP into the NTS significantly increased MAP but not plasma catecholamine concentrations, while injection of 10 ng AVP significantly increased MAP and plasma noradrenaline and adrenaline levels. Neither dose of AVP produced any change in HR. The vehicle did not affect MAP, HR or plasma catecholamine levels. Injection of a specific pressor antagonist of AVP, d(CH2)5Tyr-(Me)AVP (10 ng), did not change MAP, HR or plasma noradrenaline or adrenaline levels. These results suggest that the NTS is a central site of the pressor action of AVP. However, since the injection of the AVP antagonist did not reduce MAP or plasma noradrenaline or adrenaline levels, it suggests that AVP does not act tonically at the NTS to influence sympathoadrenal outflow.     

Combined effects of THC and caffeine on working memory in rats

BACKGROUND AND PURPOSE

Cannabis and caffeine are two of the most widely used psychoactive substances. Δ⁹-Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, induces deficits in short-term memory. Caffeine, a non-selective adenosine receptor antagonist, attenuates some memory deficits, but there have been few studies addressing the effects of caffeine and THC in combination. Here, we evaluate the effects of these drugs using a rodent model of working memory.

EXPERIMENTAL APPROACH

Rats were given THC (0, 1 and 3 mg·kg⁻¹, i.p.) along with caffeine (0, 1, 3 and 10 mg·kg⁻¹, i.p.), the selective adenosine A₁-receptor antagonist CPT (0, 3 and 10 mg·kg⁻¹) or the selective adenosine A_2A-receptor antagonist {"type":"entrez-protein","attrs":{"text":"SCH58261","term_id":"1052882304","term_text":"SCH58261"}}SCH58261 (0 and 5 mg·kg⁻¹) and were tested with a delayed non-matching-to-position procedure in which behaviour during the delay was automatically recorded as a model of memory rehearsal.

KEY RESULTS

THC alone produced memory deficits at 3 mg·kg⁻¹. The initial exposure to caffeine (10 mg·kg⁻¹) disrupted the established pattern of rehearsal-like behaviour, but tolerance developed rapidly to this effect. CPT and {"type":"entrez-protein","attrs":{"text":"SCH58261","term_id":"1052882304","term_text":"SCH58261"}}SCH58261 alone had no significant effects on rehearsal or memory. When a subthreshold dose of THC (1 mg·kg⁻¹) was combined with caffeine (10 mg·kg⁻¹) or CPT (10 mg·kg⁻¹), memory performance was significantly impaired, even though performance of the rehearsal-like pattern was not significantly altered.

CONCLUSION AND IMPLICATIONS

Caffeine did not counteract memory deficits induced by THC but actually exacerbated them. These results are consistent with recent findings that adenosine A₁ receptors modulate cannabinoid signalling in the hippocampus.

LINKED ARTICLES

This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7     

Time-related effects of intoxication with cadmium and mercury in the red wood ant

Biochemical and physiological effects of prolonged feeding of the ant Formica aquilonia, in natural conditions with excess of cadmium or mercury, were studied. In all developmental stages metals caused the time-dependent increase of AMP, parallel with a decrease of ATP and the pool size of adenylates. This was reflected by a low adenylate energy charge (AEC) index and accompanied by an inhibition of ATPases. Despite the fall in the adenylate pool of workers, the levels of adenylate energy charge confirmed their ability to maintain energetic balance. Prolonged access to food highly contaminated with Cd, or Cd with Hg, diminished these adaptive abilities, but pre-adaptive reactions (not correlated with the metal load) were induced. Activity patterns of enzymes involved in energy metabolism showed metal dependent inhibitory effects, but repeated contamination evoked some compensatory mechanisms, both in workers and in the pupal stage from the next generations. Cadmium (indirectly) stimulated the esterases and free radical scavengers. Compensatory mechanisms were insufficient in insects contaminated with both Hg and Cd, even causing family disappearance, through increased mortality and migration to other colonies. Compensatory mechanisms expressed by the adult workers appeared to be of a phenotypic origin