Angiotensin converting enzyme inhibitors as potential cognitive enhancing agents.

Anecdotal reports of a mood-elevating effect in patients and improvements in the performance of memory tests in the clinic has led to investigations into the nootropic actions of angiotensin converting enzyme (ACE) inhibitors. A cognitive enhancing action for the ACE inhibitors has been demonstrated in a number of animals models of memory function. Neurochemical studies in animals have shown that angiotensin II acting via an angiotensin II receptor can inhibit the release of 3HAch from entorhinal cortex slices. Thus the ability of ACE inhibitors to facilitate cognitive processes may be related to reduced availability of angiotensin II. Lack of specificity of ACE inhibitors may be a limiting factor in the development of such compounds as cognitive enhancers. However, the recent development of selective antagonists for subtypes of the angiotensin II receptor may represent a novel approach for the treatment of cognitive disorders with an underlying cholinergic disturbance.     

Captopril potentiates the anticonvulsant activity of carbamazepine and lamotrigine in the mouse maximal electroshock seizure model

Some studies suggest a higher risk of hypertension in people with epilepsy. Captopril, a potent and selective angiotensin-converting enzyme (ACE) inhibitor, is a well known antihypertensive drug. Besides the peripheral renin–angiotensin system (RAS), ACE inhibitors are also suggested to affect the brain RAS which might participate in the regulation of seizure susceptibility. The purpose of the current study was to evaluate the effect of captopril on the protective action of numerous antiepileptic drugs (carbamazepine [CBZ], phenytoin [PHT], valproate [VPA], phenobarbital [PB], oxcarbazepine [OXC], lamotrigine [LTG] and topiramate [TPM]) against maximal electroshock-induced seizures in mice. This study was accompanied by an evaluation of adverse effects of combined treatment with captopril and antiepileptic drugs in the passive avoidance task and chimney test. Captopril (25 and 50 mg/kg i.p.) did not influence the threshold for electroconvulsions. Among the tested antiepileptics, captopril (25 and 50 mg/kg i.p.) potentiated the antiseizure action of CBZ, decreasing its ED₅₀ value from 12.1 to 8.9 and 8.7 mg/kg, respectively. Moreover, captopril (50 mg/kg i.p.) enhanced the anticonvulsant activity of LTG. ED₅₀ value for LTG was lowered from 5.1 to 3.5 mg/kg. The observed interactions between captopril and CBZ or LTG were pharmacodynamic in nature as captopril did not alter plasma and total brain concentrations of these antiepileptics. The combinations of captopril with antiepileptic drugs did not lead to retention deficits in the passive avoidance task or motor impairment in the chimney test. Based on the current preclinical data, it is suggested that captopril may positively interact with CBZ and LTG in epileptic patients. The combinations of captopril with the remaining antiepileptics (PHT, VPA, PB, OXC and TPM) seem neutral.     

AT(2) but not AT(1) receptor antagonism abolishes angiotensin II increase of the acquisition of conditioned avoidance responses in rats

In this study we attempted to determine behavioural, including cognitive, consequences of the brain AT(1) (losartan, 2 nmol), AT(2) (PD 123319, 1.5 nmol), and joint AT(1)/AT(2) angiotensin receptors blockade. Male Wistar rats (160-180 g) were injected into the left cerebral ventricle with the above doses of the blockers dissolved in 0.9% NaCl solution (vehicle) or with the vehicle alone. Five minutes later they received, to the right cerebral ventricle, 1 nmol of angiotensin II (Ang II) dissolved in vehicle or the vehicle alone. Ang II consistently increased rate of acquisition of conditioned avoidance response (CARs) and facilitated recall of the passive avoidance behaviour. In one out of the three series of experiments in open field Ang II stimulated rats locomotor activity. Losartan and PD 123319, both ineffective alone, given prior to Ang II abolished all the behavioural changes produced by the peptide except for the Ang II facilitation of CARs acquisition, which was unchanged by losartan. Interestingly, joint injection of losartan and PD 123319 significantly decreased the rate of CARs acquisition both in control and Ang II treated animals. In conclusion, the present data suggest significant though different involvement of both AT(1) and AT(2) angiotensin receptors in cognitive processes.     

Effect of Intravenous Captopril on c-fos Expression Induced by Sodium Depletion in Neurons of the Lamina Terminalis

Peripheral administration of the angiotensin converting enzyme (ACE) inhibitor, captopril, and the central infusion of sarile, an angiotensin II (Ang II) receptor antagonist, were used to evaluate the role of renal and brain generated Ang II in sodium depletion-induced production of Fos in cells of the subfornical organ (SFO) and organum vasculosum lamina terminalis (OVLT). Pretreatment with intravenous captopril (100 mg/kg) significantly inhibited the c-fos expression induced by sodium depletion in the SFO and OVLT. In contrast, continuous intracerebroventricular infusion of sarile (22.5 μg/4.5 h, 5 μl/h) did not affect the expected pattern of c-fos expression observed in both nuclei, 4 h after peritoneal dialysis. These results show that systemic interference with the angiotensin system of renal origen by captopril inhibited the production of Fos induced by sodium depletion in cells of the SFO and OVLT. These findings are consistent with the hypothesis that a rise in peripheral Ang II levels, triggered by sodium deficiency, could be an important mediator of the physiological and behavioral responses that lead to the restoration of sodium balance. In addition, this study suggests that increased circulating Ang II levels in response to body sodium deficit can directly stimulate neural pathways in the SFO and OVLT.     

Interaction of central Ang II and NO on the cardiac sympathetic afferent reflex in dogs

The aim of this study was to test the hypothesis that the central angiotensin II (Ang II) and nitric oxide (NO) systems interact to modulate the cardiac sympathetic afferent reflex (CSAR). All dogs were anesthetized with alpha-chloralose (100 mg/kg, iv). They were sino-aortic baroreceptor denervated and vagotomized throughout the experiment renal sympathetic nerve activity responses to cardiac sympathetic afferent stimulation and the central gain of the CSAR were measured. Three protocols were performed: (1) intracerebroventricular injection (icv, 3 microg/h or 6 microg/h) of Ang II with and without N(omega)-nitro-L-arginine methyl ester (L-NAME) (icv, 1 mg/kg), (2) L-NAME (icv) with and without Ang II (icv, 6 microg/h), and (3) administration of the specific neural NO synthase (nNOS) inhibitor, S-Methyl-L-thiocitrulline (MeTC) (icv, 0.1 or 1 mM, 0.5 ml in 5 min) with and without pretreatment with the angiotensin type 1 receptor antagonist, losartan (icv, 0.125 mg/kg). The primary findings were (1) Ang II alone did not significantly affect the central sensitivity of the CSAR. However, Ang II with L-NAME enhanced this reflex, (2) even though L-NAME alone augmented the CSAR, this excitatory effect was further potentiated in the presence of Ang II and (3) MeTC significantly enhanced the central sensitivity of the CSAR. However, this enhancement did not occur after pretreatment with losartan. These data suggest that Ang II interacts with NO in the brain to modulate the CSAR and that inhibition of NO is required for facilitation of the CSAR by Ang II.     

Psychotropic effects of angiotensin II and III in rats: locomotor and exploratory vs cognitive behaviour

One nmol of angiotensin II (AII) or angiotensin III (AIII) given intracerebroventricularly (i.c.v.) increased locomotor and exploratory activity in an open field apparatus but not in the electromagnetic field motimeter. Both peptides significantly enhanced stereotyped behaviour produced by apomorphine (2 mg/kg) and amphetamine (6.5 mg/kg) given intraperitoneally. Also, AII and AIII improved consolidation but not retrieval of memory for an appetitively reinforced spatial discrimination task in a T-maze. AII as well as AIII, given prior to the learning session on day 1, increased rate of acquisition of conditioned avoidance responses in a shuttle-box over the next 7 days. Both angiotensins, injected i.c.v. 15 min before the retention testing, remarkably (5-fold) prolonged re-entry latencies in the passive avoidance situation, suggesting facilitation of the retrieval of memory for an aversively motivated behaviour.     

Inhibition of the renin-angiotensin system downregulates tissue factor and vascular endothelial growth factor in human breast carcinoma cells

Introduction

The renin-angiotensin system (RAS) promotes angiogenesis and growth of neoplastic cells. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor AT1 blockers may protect against cancer. Tissue factor (TF), for its involvement in tumor growth, angiogenesis, and metastasis is considered a hallmark of cancer progression.In this study we evaluated whether RAS blockade modulates TF constitutive expression by the metastatic breast carcinoma MDA-MB-231 cell line.

Materials and Methods

Cell TF activity was assessed by one stage clotting time, TF and VEGF antigens and mRNA levels by ELISA and RT-PCR, respectively. AT₁ was detected by flow-cytometry and angiotensin-II levels by EIA.

Results

Captopril reduced in a concentration-dependent way both the strong constitutive TF activity (983.2 ± 55.2 vs. 686.7 ± 135.1 U/5 × 10⁵ cells with 10 μg/ml captopril) and antigen (32.3 ± 5.9 vs. 13.2 ± 6.6 ng/ml) in MDA-MB-231. Similar results were observed with enalapril.AT1 was present on cell membrane and losartan, a competitive inhibitor of AT1, reduced TF expression to a degree similar as that exerted by ACE inhibitors. Moreover, captopril and losartan downregulated the constitutive mRNA TF expression by ~ 35%. Similar results were observed with anti-AT1 and angiotensin II antibodies. In addition, the constitutive VEGF antigen and mRNA levels were reduced in the presence of captopril or losartan, and an anti-VEGF antibody downregulated cell TF activity by ~ 40%.

Conclusions

These results could, at least in part, contribute to the discussion about the possible effects of ACE inhibitors and AT1 receptor antagonists in malignancy, and offer new clues to support their use for tumor control.     

Action of angiotensin converting enzyme inhibitors in rat brain: interaction with isoproterenol assessed by Fos immunocytochemistry

Low and high doses of angiotensin converting enzyme (ACE) inhibitors have been shown either to enhance or suppress, respectively, the water intake of rats induced by acute administration of isoproterenol. In order to assess the role and sites of action of angiotensin II (Ang II) in this dual action of ACE inhibitors, rats were administered either low or high doses of enalapril or captopril, followed by isoproterenol, and were sacrificed 1 h later for determination of Fos-like immunoreactivity (FLI) in brain. Isoproterenol induced strong FLI in the magnocellular paraventricular (PVN) and supraoptic (SON) nuclei, and moderate staining along the structures of the rostral wall of the lamina terminalis (LT). Low doses of ACE inhibitors either had no effect or slightly increased FLI along the LT following isoproterenol. Enalapril reduced FLI in some other regions, including the parvocellular PVN. In contrast, high doses of ACE inhibitors abolished FLI along the LT, and reduced FLI in the PVN and SON. Captopril, but not enalapril, induced some FLI in the LT, SON and PVN.The data are discussed in terms of access of ACE inhibitors to the brain, and interactions with structures involved in Ang-related water intake.     

Positive effects of captopril in the behavioral despair swim test

Captopril, an angiotensin II converting enzyme (ACE) inhibitor, was evaluated for potential antidepressive activity on the forced swim-induced behavioral despair (immobility) test in mice. Captopril (10.0 and 30.0, mg/kg ip) significantly reduced immobility and mimicked the effects of the antidepressants imipramine (30.0 mg/kg, ip) and mianserin (3.0, 10.0, and 30.0 mg/kg, ip). Captopril increased the motor activity of mice at these same dosages. Naloxone (2.0 mg/kg, ip) blocked the effects of captopril (30.0 mg/kg, ip) in the swim test. These data suggest that captopril has potential antidepressive activity. However, the conclusion is guarded, as the positive effects may be related to motor stimulation. The blockade of the captopril effects by naloxone suggests that brain opioid peptides play a role in this behavioral effect of captopril.     

Central angiotensin converting enzyme facilitates memory impairment in intracerebroventricular streptozotocin treated rats

Preclinical and clinical studies indicated involvement of renin angiotensin system (RAS) in memory functions. However, exact role of RAS in cognition is still ambiguous. Our aim was to explore how angiotensin converting enzyme (ACE) modulates memory in experimental model of memory impairment. Memory deficit was induced by intracerebroventricular administration of streptozotocin (STZ, 3 mg/kg) in rats. Perindopril, an ACE inhibitor, was given for 21 days and memory function was evaluated by Morris water maze test. Cerebral blood flow (CBF) was measured by laser doppler flowmetry. The biochemical and expression studies were done in cortex and hippocampus of rat brain after the completion of behavioral studies. STZ caused impairment in memory along with significant reduction in CBF, ATP level and elevated oxidative and nitrosative stress. The activity and mRNA expression of acetylcholinesterase (AChE) and ACE were also increased in rat brain regions following STZ administration. However, serum ACE activity remained unaffected. Treatment with perindopril dose dependently improved memory by increasing energy metabolism and CBF. Perindopril also decreased oxidative and nitrosative stress, activity and mRNA expression of AChE and ACE in STZ treated rat. Further, ACE inhibition mitigated STZ induced neurodegeneration as observed in histopathological studies. Moreover, perindopril per se improved memory and CBF, decreased oxidative stress with no effect on AChE activity and expression. However, perindopril per se significantly reduced ACE activity but increased mRNA expression of ACE in rat brain. These results suggest that ACE occupies a pivotal role in STZ induced memory deficit thus implicating central RAS in cognition.     

CX3CR1 receptor is up-regulated in monocytes of coronary artery diseased patients: impact of pre-inflammatory stimuli and renin-angiotensin system modulators

Fractalkine/CX3CR1 pathway is considered a major modulator of atherosclerosis. In the present study, expression of CX3CR1 on PBMCs/monocytes of healthy individuals and coronary artery diseased patients was initially assessed by flow cytometry. Effects of pre-inflammatory cytokines interferon (INF)-gamma and tumor necrosis factor (TNF)-alpha on expression of CX3CR1 and a single representative of each major chemokine family (CCR5 and CXCR4) were further assessed in three cell models: THP-1 monocytes, Jurkat T lymphocytes and primary monocytes isolated from healthy donors. Finally, effects of angiotensin-converting enzyme (ACE) inhibitors captopril, lisinopril and angiotensin receptor blocker (ARB) losartan on chemokine receptor expression were evaluated in the same cell models either in a naive or stimulated state. INF-gamma significantly affected the chemokine receptor phenotype of THP-1 cells by increasing the rate of CX3CR1-positive cells. Pre-treatment with the ACE inhibitors, captopril and lisinopril, and the ARB, losartan, did not influence these effects. Captopril and lisinopril similarly had no effect on either stimulated or naive primary monocytes. Yet, a small but repeatable increase in CX3CR1 expression after treatment with losartan was noted. Nevertheless, the latter observation did not retain statistical significance after applying the Bonferroni correction. In conclusion, our data did not indicate any significant effect of the ACE inhibitors on the chemokine receptor phenotype of monocytes.     

Interplay between RAS and opioids: Opening the Pandora of complexities

Angiotensin and endogenous opioids are important bioactive neuropeptides, which are widely distributed in the brain and peripheral regions to produce diverse biological and neurobiological activities. An endogenous opioid system includes proopiomelanocortin-derived enkephalin, dynorphin and endorphin that act on their specific receptors such as delta (δ), kappa (κ) and mu (μ) receptors. Research evidence demonstrates significant positive as well as negative interactions between renin angiotensin system (RAS) and endogenous opioids in the brain and periphery. The diverse actions of Ang II are possibly mediated indirectly through endogenous opioids, while opioids are also shown to activate RAS components suggesting the up-regulation of each system in concern with each other. On the contrary, there are reports suggesting a negative correlation between RAS and opioid system. Research evidence also supports the notion that Ang II acts as anti-opioid peptide to decrease the actions of opioids. Moreover, opioids-induced decline in angiotensin release and functioning has also been reported. Co-administration of ACE inhibitors with opioids exhibits significant interactions possibly due to decreased metabolism of opioids leading to potentiation of their actions. The present review describes the complexities of positive and negative interactions between RAS and opioids along with possible mechanisms responsible for these interactions.     

Distribution of Fos-immunoreactivity in rat brain following a dipsogenic dose of captopril and effects of angiotensin receptor blockade

Immunohistochemical techniques were used to detect Fos in the brain following subcutaneous administration of the angiotensin converting enzyme inhibitors captopril or enalapril at 0.5 mg/kg to conscious rats. Increased Fos-like immunoreactivity was observed in many neurons in the lamina terminalis, and in regions of the hypothalamus. Captopril at this dose also caused water drinking in other rats. Pre-treatment with the angiotensin AT₁ receptor antagonist ZD7155 (10 mg/kg) given subcutaneously prevented the captopril-induced increase in Fos in the lamina terminalis. This dose of ZD7155 also prevented captopril-induced drinking in other rats. With a higher dose (50 mg/kg) of captopril or enalapril, there was no increase in Fos in the lamina terminalis. This dose of captopril was not dipsogenic. The results are consistent with the proposal that the lower dose (0.5 mg/kg) of captopril or enalapril increases circulating angiotensin I levels which are then converted to angiotensin II in the organum vasculosum of the lamina terminalis and subfornical organ. Stimulation of neurons at these sites may subserve water drinking and sodium appetite.     

AT1 receptor in paraventricular nucleus mediates the enhanced cardiac sympathetic afferent reflex in rats with chronic heart failure

Our previous studies have shown that the cardiac sympathetic afferent reflex (CSAR) was enhanced in the chronic heart failure in dogs and rats. Exogenous angiotensin II (Ang II) in the paraventricular nucleus (PVN) potentiated this reflex which was mediated by AT1 receptor. The aim of the present study was to determine if the abnormal endogenous Ang II and AT1 receptor in the PVN were responsible for the enhanced CSAR in rats with coronary ligation-induced chronic heart failure (CHF). Under urethane and alpha-chloralose anesthesia, mean arterial pressure, heart rate and renal sympathetic nerve activity (RSNA) were recorded in sino-aortic denervated and cervical vagotomized CHF and sham-operated rats. The effects of bilateral microinjection of AT1 receptor antagonist losartan and angiotensin converting enzyme inhibitor captopril on the CSAR evoked by epicardial application of bradykinin (BK, 0.04 and 0.4 microg) were determined respectively. Both AT1 receptor mRNA and AT1 receptor protein in the PVN were measured. Bilateral microinjection of either captopril (10 nmol) or losartan (50 nmol) into the PVN inhibited the enhanced CSAR evoked by BK in rats with CHF, but had no significant effects in sham-operated rats. AT1 receptor protein in the PVN significantly increased in CHF rats compared with sham-operated rats. These results indicated that either decrease of Ang II or blockage of AT1 receptor in the PVN normalized the enhanced CSAR evoked by epicardial application of BK in rats with CHF, and that increased expression of AT1 receptor in the PVN contributed to the enhanced CSAR in the CHF state.     

Effects of histamine precursor and (R)-alpha-methylhistamine on the avoidance response in rats.

The aim of this work is to clarify the role of histamine in learning and memory processes. In order to do this, the effect of administration of the histamine precursor, L-histidine (HIS) and of the agonist of the H(3) receptor, (R)-alpha-methylhistamine (RAMH), on active avoidance response in rats is studied. Treatment with RAMH (10 mg/kg i.p.) increased the number of avoidance responses produced during acquisition and retention of the learning. In contrast, administration of L-his (500 mg/kg i.p.) impairs performance in the shuttle-box. These results are consistent with a role for histamine in cognitive processes and suggest that a increase in cerebral histamine levels impair the acquisition of avoidance response, whereas reduced levels facilitate this acquisition.     

Bradykinin-induced water intake and brain fos-like immunoreactivity in rats

We have previously shown that peripheral injection of bradykinin in combination with the kinase II inhibitor, captopril, to rats produces a robust water intake. We now extend this observation to another kinase II inhibitor, enalapril. Water intake increases with dose of dose of bradykinin, but has an inverted U-shaped relationship with dose of kininase II inhibitor. The induced water intake is completely blocked by peripheral administration of the bradykinin antagonist, Hoe 140, and is partly attenuated by peripheral injection of an angiotensin (Ang) II receptor antagonist, losartan. Relative to captopril alone, the combination of captopril and bradykinin greatly elevated plasma renin activity, but did not reduce blood pressure. We further show that, while either bradykinin or enalapril alone induce little or no Fos-like immunoreactivity in areas of the brain related to fluid balance, their combination induces staining in many cells in the supraoptic and paraventricular magnocellular nuclei, as well as along the lamina terminalis. These data suggest that bradykinin may have a role in regulation of fluid balance, partly mediated through Ang II.     

Mineralocorticoid pretreatment enhances angiotensin II-induced neuronal excitation but not salt drinking in male Fischer rats

Central administration of angiotensin (Ang) II stimulates thirst and sodium intake via the AT-1 receptor. Mineralocorticoid pretreatment enhances Ang II-induced drinking of hypertonic salt solutions (i.e. the synergy theory) in Wistar and Sprague-Dawley rats. Electrophysiological experiments using iontophoretic application of Ang II, and the AT-1 receptor specific nonpeptide antagonist losartan, have shown excitation of neurones in the preoptic/medial septum region of urethane anaesthetised male Wistar rats. Deoxycorticosterone acetate (DOCA) pretreatment further enhanced this neuronal excitation to Ang II and reduced the responses to losartan. This generated the hypothesis that DOCA-enhanced Ang II-induced neuronal excitation was necessary for the enhanced salt intake of synergy theory. We tested this hypothesis in Fischer 344 rats that are known to have a low basal salt appetite and reduced sensitivity for i.c.v. Ang II. We compared the effect of DOCA pretreatment on i.c.v. Ang II-induced water and 2% NaCl intake in behaving adult male, Fischer rats, as well as preoptic/medial septum region neuronal responses to Ang II and losartan, using a seven-barrelled micro-iontophoretic electrode sealed to a recording electrode in urethane anaesthetised, male Fischer rats. Two groups were used: one pretreated with DOCA (0.5 mg/day for 3 days) and the other comprising controls, treated with isotonic saline. Ang II applied iontophoretically increased activity in 31% of the spontaneously active neurones. Following DOCA pretreatment, the responsiveness to Ang II (when applied after aldosterone) was increased. By contrast, in the behaving animals, water and 2% NaCl intake in response to i.c.v. Ang II were not enhanced by DOCA pretreatment. These results do not support the working hypothesis but could be interpreted as evidence for the existence of two separately modulated central Ang II systems: one responding to mineralocorticoids with increased neuronal activity and the other responsible for the Ang II-induced sodium appetite in conscious rats.     

Piracetam facilitates long‐term memory for a passive avoidance task in chicks through a mechanism that requires a brain corticosteroid action

We investigated the effects of piracetam, a nootropic, on learning and memory formation for a passive avoidance task in day-old chicks. To test for the possible cognitive-enhancing properties of piracetam, a weak learning version of this task – whereby chicks maintain a memory to avoid pecking at a bead coated in a diluted aversant for up to 10 h – was used. Post-training (5, 30 or 60 min), but not pretraining, injections of piracetam (10 or 50 mg/kg, i.p.) increased recall for the task when the chicks were tested 24 h later. Because previous studies showed that long-term memory for the passive avoidance task is dependent upon a brain corticosteroid action, and because the efficacy of piracetam-like compounds is also modulated by corticosteroids, we tested whether the facilitating effect of piracetam was dependent upon a corticosteroid action through specific brain receptors (mineralocorticoid receptor and glucocorticoid receptor). First, increased plasma levels of corticosterone were found 5 min after piracetam injection. In addition, intracerebral administration of antagonists for each receptor type (RU28318, for mineralocorticoid receptors, and RU38486 for glucocorticoid receptors; i.c.) given before the nootropic inhibited the facilitative effect of piracetam on memory consolidation. These results give further support to a modulatory action of piracetam on the mechanisms involved in long-term memory formation through a neural action that, in this learning model, requires the activation of the two types of intracellular corticosteroid receptors.     

Captopril blocks the cardiac actions of centrally administered angiotensin I in the trout Oncorhynchus mykiss

The present study was performed in order to gain new insights into the existence of a brain renin-angiotensin system (RAS) in teleost fish. For this purpose, we investigated the effects of centrally administered angiotensin (ANG) I ([Asn(1),Val(5),Asn(9)]ANG I) and ANG II ([Asn(1),Val(5)]ANG II) on heart rate (HR) and heart rate variability (HRV) in the unanesthetized trout. The animals were studied before and after treatment with captopril, an angiotensin-converting enzyme (ACE) inhibitor. Trout were equipped with two subcutaneous electrocardiographic electrodes and with an intracerebroventricular (i.c.v.) cannula inserted within the third ventricle of the brain. The i.c.v. injection of vehicle had no effect on the recorded parameters. The i.c.v. injections of ANG I and ANG II at doses of 5 and 50 pmol had a marked effect on HR and HRV. At a dose of 50 pmol, ANG I and ANG II produced a progressive and significant increase in HR (+36% and+45%, respectively) but elicited a profound decrease in HRV (-88% and-92%, respectively). I.c.v. injection of captopril (10 microg) had no effect on HR or HRV. However, this ACE inhibitor prevented the tachycardia and abolished the decrease in HRV mediated by 50 pmol of ANG I. In contrast, captopril had no effect upon the cardiac actions of 50 pmol of ANG II. These results give the first support for the existence of functional important ACE-like activity in the brain of a teleost fish and suggest that the brain RAS in this class of vertebrate may be involved in the control of cardiac chronotropic activity.     

Hypericum extract and hyperforin: memory-enhancing properties in rodents

Effects of a Hypericum extract in therapeutic use and hyperforin sodium salt were evaluated in rat and mouse avoidance tests. In a conditioned avoidance response (CAR) test on the rat, oral daily administration of hyperforin (1.25 mg/kg/day) or of the extract (50 mg/kg/day) before the training sessions considerably improved learning ability from the second day onwards until the day 7. In addition, the memory of the learned responses acquired during 7 consecutive days of administration and training was largely retained even after 9 days without further treatment or training. The observations made using different doses indicate that these learning-facilitating and/or memory-consolidating effects by the agents follow inverse U-shaped dose-response curves in dose ranges lower than (for hyperforin) or equal to (for Hypericum extract) their effective dose in the behavioral despair test for antidepressants. In a passive avoidance response test on the mouse, a single oral dose (1.25 mg/kg) of hyperforin not only improved memory acquisition and consolidation, but also almost completely reversed scopolamine-induced amnesia. The single Hypericum extract dose tested (25 mg/kg) did not reveal any significant effects in the passive avoidance response (PAR) test on the mouse. These observations suggest that the Hypericum extract could be a novel type of antidepressant with memory enhancing properties, and indicate that hyperforin is involved in its cognitive effects. Pure hyperforin seems to be a more potent antidementia agent than an antidepressant.